Nucleic acid suppressing expression of apcs

ABSTRACT

The present invention provides a double-stranded nucleic acid consisting of a sense-strand nucleic acid and an antisense-strand nucleic acid and comprising a double-strand region having at least 11 base pairs, for suppressing expression of APCS gene, in which an oligonucleotide chain having a chain length of at least 17 nucleotides and at most 30 nucleotides in the antisense-strand nucleic acid is complementary to a target APCS mRNA sequence comprising a base sequence set forth in any one of SEQ ID NOS: 1288 to 1930.

TECHNICAL FIELD

The present invention relates to a nucleic acid that suppresses expression of APCS or a pharmaceutical composition comprising the nucleic acid.

BACKGROUND ART

APCS (amyloid P component, serum; also referred to as Serum amyloid P, SAP or Pentraxin-2) has a pentamer structure of a glycoprotein constituted of 223 amino acids. APCS is a protein produced in the liver and present in the blood at a relatively high concentration of 30 to 50 μg/mL.

APCS has a biochemical property of binding to all types of amyloid fibrils in a calcium-dependent manner. It is known that APCS is contained in an amount as large as 20,000 mg in amyloid of patients having amyloid (non-Patent Literature 1).

Since APCS is present in amyloid of all patients with an amyloid-related disease, APCS is used as a diagnostic marker in patients with an amyloid-related disease (non-Patent Literature 2).

The amyloid-related disease is a disease causing organ damage, which is caused by accumulation of abnormal insoluble protein-fibers (known as amyloid fibrils) on a tissue.

It has been clarified that amyloid to which APCS binds can be stabilized by APCS inducing resistance to decomposition with protease and phagocytosis by immune cells. Also, researches and clinical studies using animal models strongly suggest that amyloid accumulation on organs and tissue disorders associated to the accumulation can be reduced by inhibiting binding of APCS to amyloid (non-Patent Literatures 3, 4). It is expected that amyloid-related diseases can be prevented or treated by specifically suppressing expression of APCS; however, pharmaceutical products that specifically suppresses expression of APCS have not yet been reported up to present.

As a method for suppressing expression of a gene, itself, for example, a method of using RNA interference (also referred to as RNAi) is known. More specifically, it has been found that expression of a target gene is specifically suppressed by introduction of double strand RNA having the same sequence as a target gene, and the RNA is called as short interfering RNA (siRNA) (Patent Literature 1). Alternatively, as a method for suppressing expression of a gene other than RNA interference, an antisense method is known (Patent Literature 2).

A part of the siRNA sequence targeting human APCS mRNA is disclosed; however, it has not been known that the siRNA sequence suppresses expression of human APCS (Patent Literatures 3, 4).

CITATION LIST Patent Literatures

-   Patent Literature 1: International Publication No. WO2001/75164 -   Patent Literature 2: International Publication No. WO98/56905 -   Patent Literature 3: International Publication No. WO2005/116204 -   Patent Literature 4: International Publication No. WO2008/043561 -   Non Patent Literature 1: Amyloid, 4: 4, 274-295 (1997) -   Non Patent Literature 2: N. Engl. J. Med. 1990; 323: 508-13 -   Non Patent Literature 3: Nature 468: 93-97. (2010) -   Non Patent Literature 4: N. Engl. J. Med. 373: 1106-14. (2015)

SUMMARY OF INVENTION Technical Problem

An object of the present invention is to provide a nucleic acid capable of suppressing the expression of APCS.

Solution to Problem

The present invention relates to the following (1) to (13).

(1) A double-stranded nucleic acid consisting of a sense-strand nucleic acid and an antisense-strand nucleic acid and comprising a double-strand region having at least 11 base pairs, for suppressing expression of APCS gene, wherein an oligonucleotide chain having a chain length of at least 17 nucleotides and at most 30 nucleotides in the antisense-strand nucleic acid is complementary to a target APCS mRNA sequence comprising a base sequence set forth in any one of SEQ ID NOS: 1288 to 1930.

(2) The double-stranded nucleic acid according to (1), wherein the double-strand region has 11 to 27 base pairs and a nucleotide at position 2 counted from a 5′ end of the antisense-strand nucleic acid is complementary to a nucleotide at position 2 counted from a 3′ end of the target APCS mRNA sequence.

(3) The double-stranded nucleic acid according to (1) or (2), wherein a 3′ end of the sense-strand nucleic acid and a 5′ end of the antisense-strand nucleic acid and/or the 5′ end of the sense-strand nucleic acid and the 3′ end of the antisense-strand nucleic acid form a blunt end.

(4) The double-stranded nucleic acid according to any one of (1) to (3), wherein the sense-strand nucleic acid has a chain length of 21 nucleotides and the antisense-strand nucleic acid has a chain length of 21 nucleotides.

(5) The double-stranded nucleic acid according to (4), comprising a double-strand region having 19 base pairs, in which 40 to 65% of the nucleotides in the double-strand region are 2′-O-methyl modified nucleotides.

(6) The double-stranded nucleic acid according to any one of (1) to (5), wherein the antisense-strand nucleic acid comprises a base sequence set forth in any one of SEQ ID NOS: 645 to 1287 and 1975 to 2018.

(7) The double-stranded nucleic acid according to any one of (1) to (6), wherein the sense-strand nucleic acid comprises a base sequence set forth in any one of SEQ ID NOS: 2 to 644 and 1931 to 1974.

(8) The double-stranded nucleic acid according to any one of (1) to (7), wherein the sense-strand nucleic acid comprises a base sequence set forth in any one of SEQ ID NOS: 2 to 644 and 1931 to 1974, and correspondingly thereto, the antisense-strand nucleic acid comprises a base sequence set forth in any one of SEQ ID NOS: 645 to 1287 and 1975 to 2018.

(9) The double-stranded nucleic acid according to any one of (1) to (8), comprising a ligand.

(10) A single-stranded nucleic acid consisting of only the antisense-strand nucleic acid of the double-stranded nucleic acid according to any one of (1) to (9).

(11) A pharmaceutical composition comprising the nucleic acid according to any one of (1) to (10).

(12) A method for treating a disorder mediated by APCS-containing amyloid fibrils, comprising a step of administering a therapeutically effective amount of the nucleic acid according to any one of (1) to (10) or the pharmaceutical composition according to (11) to a human in need of such a treatment.

(13) The method according to (12), wherein the disorder is an amyloid-related disease.

Advantageous Effects of Invention

According to the present invention, it is possible to provide a nucleic acid capable of suppressing the expression of APCS.

DESCRIPTION OF EMBODIMENTS

A target of the nucleic acid of the present invention, APCS mRNA, is homologous to the sequence of SEQ ID NO: 1 registered in the Genbank under Accession No. NM_001639.3 and full-length mRNA of APCS having a base sequence, in which T of the sequence of SEQ ID NO: 1 is replaced by U. Herein, the complementary DNA of mRNA is defined as 1st strand cDNA, and a DNA, which is to be synthesized based on the 1st strand cDNA in order to obtain a double strand, is defined as the 2nd strand cDNA. In this case, SEQ ID NO: 1 represents the base sequence of the 2nd strand cDNA of APCS. Note that the base sequence of APCS mRNA and the base sequence of the 2nd strand cDNA of APCS are homologous.

1. Nucleic Acid of the Present Invention

In the present invention, a nucleic acid comprising the base sequence complementary to the APCS mRNA sequence is referred to as an antisense-strand nucleic acid; whereas a nucleic acid comprising the base sequence complementary to the base sequence of the antisense-strand nucleic acid is referred to as a sense-strand nucleic acid. As used herein, “the nucleic acid of the present invention”, until otherwise specified, means nucleic acids including a single-stranded nucleic acid that is an antisense-strand nucleic acid or a sense-strand nucleic acid, and a double-stranded nucleic acid formed by pairing of the antisense-strand nucleic acid and the sense-strand nucleic acid.

The nucleic acid of the present invention may be any molecule as long as the molecule is a polymer of a nucleotide or a polymer of a molecule having the same function as a nucleotide. Examples of the nucleic acid include a ribonucleotide polymer, i.e., RNA; a deoxyribonucleotide polymer, i.e., DNA; a polymer of a ribonucleotide and deoxyribonucleotide, i.e., a chimeric nucleic acid; and a nucleotide polymer prepared by replacing at least one nucleotide of these nucleic acids (RNA, DNA, and chimeric nucleic acid) by a molecule having the same function as the nucleotide. Uracil (U) in RNA is univocally replaced by thymine (T) in DNA.

An example of the molecule having the same function as a nucleotide is a nucleotide derivative obtained by modifying a nucleotide.

Although it is not particularly limited, use of a nucleotide derivative has the advantages: for example, resistance against nuclease can be improved or stabilized compared to RNA or DNA; affinity for a complementary strand nucleic acid can be improved; cell permeability can be improved; and/or visualization can be made.

Examples of the nucleotide derivative include a nucleotide modified in the sugar portion, a nucleotide modified in a phosphate-diester bond, a nucleotide modified in a base and a nucleotide modified in two or more elements of a sugar portion, a phosphate diester bond and a base.

As the nucleotide modified in the sugar portion, any nucleotide may be used as long as part or whole of the chemical structure of the nucleotide sugar is modified or substituted with a substituent, or substituted with an atom; however, a 2′-modified nucleotide is preferably used.

Examples of the 2′-modified nucleotide include a 2′-modified nucleotide obtained by substituting 2′-OH group of the ribose with a substituent selected from the group consisting of OR, R, R′OR, SH, SR, NH₂, NHR, NR₂, N₃, CN, F, Cl, Br, and I (R represents an alkyl or aryl, preferably an alkyl having 1 to 6 carbon atoms, R′ represents an alkylene, preferably an alkylene having 1 to 6 carbon atoms and two Rs of NR₂ may be the same or different).

As the 2′-modified nucleotide, e.g., 2′-modified nucleotides obtained by substituting the 2′-OH group of the ribose with F and a methoxy group, respectively (referred to as 2′-F modified nucleotide and 2′-O-methyl modified nucleotide, respectively) are preferably used.

An example of the 2′-modified nucleotide is a 2′-modified nucleotide obtained by substituting the 2′-OH group of the ribose with a substituent selected from the group consisting of a 2-(methoxy)ethoxy group, a 3-aminopropoxy group, a 2-[(N,N-dimethylamino)oxy]ethoxy group, a 3-(N,N-dimethylamino)propoxy group, a 2-[2-(N,N-dimethylamino)ethoxy]ethoxy group, 2-(methylamino)-2-oxoethoxy group, 2-(N-methylcarbamoyl)ethoxy group and a 2-cyanoethoxy group

An example of the nucleotide modified in the sugar portion is an artificial Bridged Nucleic Acid (BNA) having two ring structures, which are obtained by introducing a cross-linked structure in the sugar portion. Specific examples thereof include an artificial Locked Nucleic Acid (LNA) in which a 2′-position oxygen atom and a 4′-position carbon atom are crosslinked via methylene ([Tetrahedron Letters, 38, 8735, (1997) and Tetrahedron, 54, 3607, (1998)], artificial Ethylene bridged nucleic acid) (ENA) [Nucleic Acid Research, 32, e175 (2004)], Constrained Ethyl (cEt) [The Journal of Organic Chemistry 75, 1569 (2010)], Amido-Bridged Nucleic Acid (AmNA) [Chem Bio Chem 13, 2513 (2012)] and 2′-O, 4′-c-Spirocyclopropylene bridged nucleic acid (scpBNA) [Chem. Commun., 51, 9737 (2015)].

Examples of the nucleotide modified in the sugar portion include a peptide nucleic acid (PNA) [Acc. Chem. Res., 32, 624 (1999)], an oxypeptide nucleic acid (OPNA) [J. Am. Chem. Soc., 123, 4653 (2001)] and a peptide ribonucleic acid (PRNA) [J. Am. Chem. Soc., 122, 6900 (2000)].

As the nucleotide modified in the phosphate diester bond, any nucleotide may be used as long as part or whole of the chemical structure of a phosphate diester bond of the nucleotide is modified or substituted with a substituent or substituted with an atom.

Examples of the nucleotide modified in the phosphate diester bond include a nucleotide obtained by substituting the phosphate diester bond with a phosphorothioate bond, a nucleotide obtained by substituting the phosphate diester bond with a phosphorodithioate bond, a nucleotide obtained by substituting the phosphate diester bond with an alkylphosphonate bond and a nucleotide obtained by substituting the phosphate diester bond with a phosphoramidate bond.

As the nucleotide modified in a base, any nucleotide may be used as long as part or whole of the chemical structure of a base of the nucleotide is modified or substituted with a substituent or substituted with an atom.

Examples of the nucleotide modified in a base include a nucleotide obtained by substituting the oxygen atom in the base with a sulfur atom, a nucleotide obtained by substituting a hydrogen atom with an alkyl group having 1 to 6 carbon atoms or halogen, a nucleotide obtained by substituting the methyl group with hydrogen, hydroxymethyl or an alkyl group having 2 to 6 carbon atoms, and a nucleotide obtained by substituting the amino group with an alkyl group having 1 to 6 carbon atoms, an alkanoyl group having 1 to 6 carbon atoms, an oxo group or a hydroxy group. Note that, using 5-methylcytosine (5-mC) in place of cytosine (C) as a nucleotide modified in a base is a preferable embodiment of the present invention.

Further examples of the nucleotide derivative include nucleotide derivatives obtained by adding, directly or via a linker, to a nucleotide or a nucleotide derivative as mentioned above, a chemical substance such as a ligand; a lipid such as cholesterol, a fatty acid, tocopherol and retinoid; a sugar such as N-acetylgalactosamine (GalNAc), galactose (Gal) and mannose (Man); a full antibody; a fragment antibody such as, Fab, scFv and VHH; a protein such as a low-density lipoprotein (LDL) and human serum albumin; a peptide such as RGD, NGR, R9 and CPP; a low molecule such as phenazine, phenanthridine, anthraquinone and folic acid; a synthetic polymer such as a synthetic polyamino acid; a nucleic acid aptamer; a pigment such as, acridine, fluorescein, rhodamine and coumarin; and a fluorophore such as Cy3 series, Alexa series (registered trademark) and a black hole quencher. Specific examples thereof include a polyamine-added nucleotide derivative, a cholesterol-added nucleotide derivative, a steroid added nucleotide derivative, a GalNAc added nucleotide derivative, a bile acid-added nucleotide derivative, a fatty acid-added nucleotide derivative, a vitamin-added nucleotide derivative, a Cy5 added nucleotide derivative, a Cy3 added nucleotide derivative, a 6-FAM added nucleotide derivative and a biotinylated nucleotide derivative. Preferably, a GalNAc added nucleotide derivative is mentioned. These derivatives can be modified at the 5′ end and/or the 3′ end, and/or within the sequence by reacting with a reactive modifier on a solid phase during an elongation reaction on the solid phase. Alternatively, a nucleic acid having a functional group such as an amino group, a mercapto group, an azido group, or a triple bond introduced therein, is synthesized and purified in advance; and a modifier may be allowed to react with the functional group.

A nucleotide derivative may have a cross-linked structure, which is formed with another nucleotide within the nucleic acid or a nucleotide derivative, and an alkylene structure, a peptide structure, a nucleotide structure, an ether structure, an ester structure, and a structure consisting of at least two of these, in combination.

The nucleic acid of the present invention includes a nucleic acid obtained by substituting part or all atoms in the nucleic acid molecule with an atom (isotope) different in mass number.

As used herein, “complementary” refers to the relationship between two bases that can be paired, for example, the relationship between adenine and thymine or uracil and the relationship between guanine and cytosine. Likewise, complementary bases are paired through a gentle hydrogen bond and form a double helix structure in the whole double-strand region. In the relationship between adenine and thymine or uracil and the relationship between guanine and cytosine, even though at least one of the bases in each of pairs of A and T (U) and G and C is a modified base, if the base pairing can be formed via a gentle hydrogen bond between two bases, the relationship between these bases can be complementary.

As used herein, “complementary” means not only the case where two nucleotide sequences are completely complementary but also the cases where a mismatch ratio between two nucleotide sequences is 0 to 30%, preferably 0 to 20% and more preferably 0 to 10%. More specifically, an antisense-strand nucleic acid complementary to the APCS mRNA sequence includes a completely complementary base sequence with a partial base sequence of the mRNA or a base sequence having a substitution(s) of one or more bases in the completely complementary base sequence. The antisense-strand nucleic acid may have 1 to 8, preferably 1 to 6, more preferably 1 to 4, further preferably 1 to 3, particularly preferably 1 to 2, particularly more preferably a single mismatch base with the target sequence of a target gene.

More specifically, in the case of the antisense-strand nucleic acid having a chain length of 21 nucleotides (21 base length), the number of mismatch bases with the target nucleotide sequence of a target gene may be 1 to 6, preferably 1 to 5, more preferably 1 to 4, further preferably 1 to 3, particularly preferably 1 to 2 and particularly more preferably a single. The mismatch position may be 5′ end or the 3′ end of each of the nucleotide sequences of antisense-strands.

As used herein, “complementary” refers to a case where one of the two nucleotide sequences is completely complementary to the other nucleotide sequence; however, the complementary sequence having addition and/or deletion of one or more bases is also included. In the present invention, the antisense-strand nucleic acid is a completely complementary base sequence to the APCS mRNA sequence; however, the antisense-strand nucleic acid may have additional bases, in other words, a single or two bulge bases to a target APCS mRNA sequence.

In the present invention, an antisense-strand nucleic acid or a sense-strand nucleic acid may have a single or two bulge bases.

In the present invention, the “bulge base” refers to a base which does not form a complementary base pair with the other nucleotide sequence.

As the antisense-strand nucleic acid of the present invention, a nucleic acid comprising a completely complementary base sequence with a target APCS mRNA sequence is used; however, the same nucleic acid as the above nucleic acid except that deletion, substitution or addition of 1 to 3 bases, preferably 1 to 2 bases and more preferably a single base are present, may be used.

The nucleic acid that suppresses expression of APCS, which is preferably used is double-stranded nucleic acid, which consists of a single-stranded nucleic acid being a nucleic acid (antisense-strand nucleic acid) comprising a base sequence complementary to a target APCS mRNA sequence or a nucleic acid (antisense-strand nucleic acid) comprising a base sequence complementary to a target APCS mRNA sequence, and a nucleic acid (sense-strand nucleic acid) comprising a base sequence complementary to the base sequence of the nucleic acid.

In the present invention, expression of APCS gene can be suppressed by the antisense-strand nucleic acid.

The double-stranded nucleic acid of the present invention is a double-stranded nucleic acid consisting of a sense-strand nucleic acid and an antisense-strand nucleic acid and comprising a double-strand region having at least 11 base pairs, for suppressing expression of APCS gene, in which an oligonucleotide chain having a chain length of at least 17 nucleotides and at most 30 nucleotides in the antisense-strand nucleic acid, is complementary to a targets APCS mRNA sequence comprising a base sequence set forth in any one of SEQ ID NOS: 1288 to 1930.

The base sequence set forth in any one of SEQ ID NOS: 1288 to 1930 is listed in Table 1.

In the double-stranded nucleic acid of the present invention, the sense-strand nucleic acid and the antisense-strand nucleic acid each may be constituted of any nucleotides or nucleotide derivatives.

The antisense-strand nucleic acid used in the double-stranded nucleic acid of the present invention is a nucleotide chain comprising a base sequence complementary to a target APCS mRNA sequence.

The target APCS mRNA sequence is homologous with SEQ ID NO: 1 and comprises a base sequence set forth in any one of SEQ ID NOS: 1288 to 1930 of the APCS mRNA sequences wherein T in SEQ ID NO: 1 is replaced by U. Preferably, the target APCS mRNA sequence is homologous with SEQ ID NO: 1 and a base sequence set forth in any one of SEQ ID NOS: 1288 to 1930 of the base sequences of APCS mRNA wherein T in SEQ ID NO: 1 is replaced by U.

In the double-stranded nucleic acid of the present invention, an oligonucleotide chain having a chain length of at least 17 nucleotides and at most 30 nucleotides, which constitute the antisense-strand nucleic acid, is complementary to the target APCS mRNA sequence.

In the present invention, an oligonucleotide chain having a chain length of preferably 11 to 27 nucleotides, more preferably 15 to 25 nucleotides, further preferably 15 to 23 nucleotides, particularly preferably 17 to 21 nucleotides, particularly more preferably 17 to 19 nucleotides and particularly further preferably 19 nucleotides, which constitute an antisense-strand nucleic acid, is complementary to the target APCS mRNA sequence.

In the present invention, the antisense-strand nucleic acid and the sense-strand nucleic acid comprise a double-strand region having at least 11 base pairs, usually 11 to 30 nucleotides, preferably 11 to 27 base pairs, more preferably 15 to 25 base pairs, further preferably 15 to 23 base pairs, particularly preferably 17 to 21 base pairs, particularly more preferably 17 to 19 base pairs, and particularly further preferably 19 base pairs.

In the present invention, a 2′-modified nucleotide is preferably contained in the nucleotides in the double-strand region and may be present in any site thereof. The suitable content of the 2′-modified nucleotide may be 10 to 20%, 20 to 40% and 40 to 65% based on the total amount (100%) of the nucleotides.

A specific example of the double-stranded nucleic acid containing a 2′-modified nucleotide is a double-stranded nucleic acid consisting of a pair of sense-strand/antisense-strand sequences selected from the group consisting of the sense-strands/antisense-strands listed in Table 3.

In the present invention, the suitable content of the 2′-modified nucleotide relative to the sense-strand nucleic acid may be 20 to 40%, 40 to 60% or 60% to 100%.

In the present invention, the suitable content of the 2′-modified nucleotide relative to the antisense-strand nucleic acid may be preferably 0 to 40%, 10 to 20% or 20 to 40%.

An antisense-strand nucleic acid and sense-strand nucleic acid (as a single strand) constituting a double-stranded nucleic acid each usually consist of 17 to 30 bases and preferably 17 to 27 bases, more preferably 17 to 25 bases, further preferably 17 to 25 bases and particularly preferably 19 to 25 bases. The base length of the antisense-strand nucleic acid and sense-strand nucleic acid may be the same or different.

In the present invention, the antisense-strand nucleic acid preferably comprises a base sequence set forth in any one of SEQ ID NOS: 645 to 1287 and 1975 to 2018; and the sense-strand nucleic acid preferably comprises a base sequence set forth in any one of SEQ ID NOS: 2 to 644 and 1931 to 1974.

In the present invention, the antisense-strand nucleic acid is more preferably a nucleotide strand having a base sequence set forth in any one of SEQ ID NOS: 645 to 1287 and 1975 to 2018; whereas the sense-strand nucleic acid is more preferably a nucleotide strand having a base sequence set forth in any one of SEQ ID NOS: 2 to 644 and 1931 to 1974.

In the double-stranded nucleic acid of the present invention, the sense-strand nucleic acid comprises a base sequence set forth in any one of SEQ ID NOS: 2 to 644 and 1931 to 1974; and correspondingly thereto, the antisense-strand nucleic acid preferably comprises a base sequence set forth in any one of SEQ ID NOS: 645 to 1287 and 1975 to 2018.

As used herein, the phrase “correspondingly thereto” means a combination of the sense-strand nucleic acid and the antisense-strand nucleic acid described in the each column of double-stranded nucleic acid numbers in Table 1 or Table 3, and SEQ ID NO: n (n=2 to 644) corresponds to SEQ ID NO: n+643. To give a specific example, SEQ ID NO: 2 corresponds to SEQ ID NO: 645.

In the double-stranded nucleic acid of the present invention, it is more preferable that a sense-strand nucleic acid is a nucleotide chain having a base sequence set forth in any one of SEQ ID NOS: 2 to 644 and 1931 to 1974; and correspondingly thereto, the antisense-strand nucleic acid is a nucleotide chain having a base sequence set forth in any one of SEQ ID NOS: 645 to 1287 and 1975 to 2018.

The double-stranded nucleic acid of the present invention has a double-strand region followed by an (additional) nucleotide or nucleotide derivative forming no double strand at the 3′-end side or the 5′-end side, the nucleotide or nucleotide derivative forming no double strand is called as a protrusion (overhang). If an overhang is present, the nucleotides constituting the overhang may be ribonucleotides, deoxyribonucleotides or derivatives of these.

As the double-stranded nucleic acid having an overhang, a double-stranded nucleic acid having an overhang consisting of usually 1 to 6 bases and preferably 1 to 3 bases at the 3′ end or the 5′ end of at least one of the sense-strand nucleic acid and antisense-strand nucleic acid, is used. A double-stranded nucleic acid having an overhang consisting of 2 bases is more preferably used, and an example thereof is a double-stranded nucleic acid having an overhang consisting of dTdT (dT represents thymidine) or UU. The overhang can be present in an antisense-strand nucleic acid alone or a sense-strand nucleic acid alone and both of the antisense-strand nucleic acid and the sense-strand nucleic acid. In any one of the cases where the overhang is present at an antisense-strand nucleic acid alone, a sense-strand nucleic acid alone and both of the antisense-strand nucleic acid and the sense-strand nucleic acid, the overhang may be present at the 3′ end and/or the 5′ end of the nucleic acid.

The antisense-strand nucleic acid to be used in the present invention, preferably, an oligonucleotide chain consisting of at least 17 nucleotides and at most 30 nucleotides including a double-strand region with the sense-strand nucleic acid and the following overhang is sufficiently complementary to a target APCS mRNA sequence comprising a base sequence set forth in any one of SEQ ID NOS: 1288 to 1930.

Examples of the double-stranded nucleic acid of the present invention that can be used include a nucleic acid molecule (WO2005/089287) producing the aforementioned double-stranded nucleic acid by the action of a ribonuclease such as Dicer; a double-stranded nucleic acid having a blunt end without an overhang at the 3′ end or the 5′ end; and a double-stranded nucleic acid (US2012/0040459) having an overhang of only a sense-strand nucleic acid. In the present invention, the “blunt end” means an end of a double-stranded nucleic acid having no overhang. The blunt end refers to, for example, a double-stranded nucleic acid where both the 3′ end of a sense-strand nucleic acid and the 5′ end of the antisense-strand nucleic acid have no overhang and/or both the 5′ end of the sense-strand nucleic acid and the 3′ end of the antisense-strand nucleic acid have no overhang.

In the present invention, it is preferable that both of the 3′ end of a sense-strand nucleic acid and the 5′ end of the antisense-strand nucleic acid and/or both of the 5′ end of the sense-strand nucleic acid and the 3′ end of the antisense-strand nucleic acid form a blunt end(s). Particularly, it is more preferable that the 3′ end of a sense-strand nucleic acid and the 5′ end of the antisense-strand nucleic acid, or the 5′ end of the sense-strand nucleic acid and the 3′ end of the antisense-strand nucleic acid forms a blunt end. If the 3′ end of a sense-strand nucleic acid and the 5′ end of the antisense-strand nucleic acid and/or the 5′ end of the sense-strand nucleic acid and the 3′ end of the antisense-strand nucleic acid form a blunt end(s), it is preferable that the sense-strand nucleic acid has a chain length of 21 nucleotides; whereas the antisense-strand nucleic acid has a chain length of 23 nucleotides.

In the present invention, it is also preferable that a double-stranded nucleic acid having an overhang at both of the antisense-strand nucleic acid and sense-strand nucleic acid. It is preferable that the 3′ end of the sense-strand nucleic acid and the 3′ end of the antisense-strand nucleic acid or the 5′ end of the sense-strand nucleic acid and the 5′ end of the antisense-strand nucleic acid have an overhang. If both of the antisense-strand nucleic acid and sense-strand nucleic acid have an overhang, it is preferable that the sense-strand nucleic acid has a chain length of 21 nucleotides and the antisense-strand nucleic acid has a chain length of 21 nucleotides.

In the present invention, it is more preferable that both of the 3′ end and the 5′ end of the sense-strand nucleic acid or both of the 3′ end and the 5′ end of the antisense-strand nucleic acid have an overhang.

It is preferable that the nucleotide at position 2 counted from the 5′ end of an antisense-strand nucleic acid of the present invention is completely complementary to the ribonucleotide at position 2 counted from the 3′ end of a target APCS mRNA sequence. It is more preferable that the ribonucleotides at positions 2 to 7 counted from the 5′ end of the antisense-strand nucleic acid are completely complementary to the ribonucleotides at positions 2 to 7 counted from the 3′ end of the target APCS mRNA sequence, respectively. It is further preferable that the ribonucleotides at positions 2 to 11 counted from the 5′ end of the antisense-strand nucleic acid are completely complementary to the ribonucleotides at positions 2 to 11 counted from the 3′ end of the target APCS mRNA sequence, respectively.

It is preferable that the nucleotide at position 11 counted from the 5′ end of an antisense-strand nucleic acid of the present invention is completely complementary to the ribonucleotide at position 11 counted from the 3′ end of a target APCS mRNA sequence. It is more preferable that the ribonucleotides at positions 9 to 13 counted from the 5′ end of the antisense-strand nucleic acid are completely complementary to the ribonucleotides at positions 9 to 13 counted from the 3′ end of the target APCS mRNA sequence, respectively. It is further preferable that the ribonucleotides at positions 7 to 15 counted from the 5′ end of the antisense-strand nucleic acid are completely complementary to the ribonucleotides at positions 7 to 15 counted from the 3′ end of the target APCS mRNA sequence, respectively.

A method for producing the nucleic acid of the present invention is not particularly limited, and examples thereof include a method using chemical synthesis known in the art and an enzymatic transcription method.

Examples of the method using chemical synthesis known in the art include a phosphoramidite method, phosphorothioate method, phosphotriester method and CEM method [Nucleic Acid Research, 35, 3287 (2007)]. The nucleic acid of the present invention can be synthesized, for example, by ABI3900 high-throughput nucleic acid synthesizer (manufactured by Applied Biosystems). After completion of synthesis, e.g., detachment from a solid phase, deprotection of a protecting group and purification of a desired product are carried out. It is desirable to obtain a nucleic acid having a purity 90% or more and preferably 95% or more by purification.

In the case of a double-stranded nucleic acid, the sense-strand nucleic acid and antisense-strand nucleic acid synthesized and purified are mixed in an appropriate ratio; for example, 0.1 to 10 equivalents, preferably 0.5 to 2 equivalents, more preferably 0.9 to 1.1 equivalents, and further preferably, 1 equivalent of the sense-strand nucleic acid is mixed with 1 equivalent of the antisense-strand nucleic acid. After mixing, the mixture is usually subjected to annealing; however, the annealing step may be skipped, and the mixture may be directly used.

The annealing may be carried out in any conditions as long as a double-stranded nucleic acid can be formed. The annealing is usually carried out by mixing an antisense-strand nucleic acid and a sense-strand nucleic acid in an almost equimolar ratio, heating the mixture at about 94° C. for about 5 minutes, and slowly cooled up to room temperature.

An example of the enzymatic transcription is a transcription method using phage RNA polymerase such as T7 and T3, or SP6RNA polymerase with a plasmid or DNA having a desired base sequence used as a template.

The nucleic acid of the present invention can be introduced into a cell by use of a transfection carrier, preferably, a cationic carrier such as a cationic liposome or directly introduced into a cell by use of a calcium phosphate method, an electroporation method or microinjection method.

The nucleic acid of the present invention may comprise a ligand. The nucleic acid of the present invention may be modified with one or more ligands or fluorophores at the 5′ end and/or the 3′ end, and/or within the sequence. The nucleic acid modified with a ligand or a fluorophore is also called as a conjugate nucleic acid. Modification can be made at the 5′ end and/or the 3′ end and/or within the sequence by allowing a reactive modifier to react on a solid phase during an elongation reaction on the solid phase. Alternatively, a nucleic acid having a functional group such as an amino group, a mercapto group, an azido group, or a triple bond introduced herein, is synthesized and purified in advance; and a modifier is allowed to react with the functional group. In this manner, a conjugate nucleic acid can be obtained. As the ligand, a molecule having an affinity to a biomolecule may be used. Examples of the ligand include a lipid such as cholesterol, a fatty acid, tocopherol and retinoid; a sugar such as N-acetylgalactosamine (GalNAc), galactose (Gal) and mannose (Man); a full antibody; a fragment antibody such as scFV, Fab and VHH; a protein such as a low density lipoprotein (LDL) and human serum albumin; a peptide such as RGD, NGR, R9 and CPP; a low molecule such as folic acid; a synthetic polymer such as a synthetic polyamino acid; and a nucleic acid aptamer. These may be used in combination. Examples of the fluorophore include Cy3 series, Alexa (registered trademark) series, and black hole quencher (registered trademark). Examples of a method for adding a ligand to the nucleic acid of the present invention include, but are not limited to, a method of allowing a modifier, which is capable of reacting on a solid phase to react, during an elongation reaction on the solid phase to modify 5′ end, 3′ end and/or within the sequence. Alternatively, a nucleic acid having a functional group such as an amino group, a mercapto group, an azido group, or a triple bond introduced herein, is synthesized and purified in advance; and a modifier may be allowed to react with the functional group.

In place of the nucleic acid of the present invention, a vector which expresses the nucleic acid by introducing the vector into a cell may be used. More specifically, an expression vector is constructed by inserting the sequence encoding the nucleic acid of the present invention to downstream of the promoter within the expression vector and introduced into a cell to allow the nucleic acid to express. Examples of the expression vector include pcDNA6.

2-GW/miR (manufactured by Invitrogen), pSilencer 4. 1-CMV (manufactured by Ambion), pSINsi-hH1 DNA (manufactured by Takara Bio Inc.), pSINsi-hU6 DNA (manufactured by Takara Bio Inc.) and pENTR/U6 (manufactured by Invitrogen).

Since the nucleic acid of the present invention is expressed within a cell, using the vector is included in the technical scope of the nucleic acid of the present invention.

A recombinant viral vector, which is produced by introducing the sequence encoding the nucleic acid of the present invention into a virus vector downstream the promoter and introducing the vector into a packaging cell, can be used. Examples of the virus vector include a retro virus vector, a lentiviral vector, an adenovirus vector and an adeno-associated virus vector.

2. Nucleic Acid Having an Activity to Suppress APCS Expression

In the present invention, an antisense-strand nucleic acid and a sense-strand nucleic acid can be designed based on the base sequence (SEQ ID NO: 1) of the APCS 2nd strand cDNA of a full-length mRNA of human APCS, which is registered, for example, in the Genbank, under Accession No. NM_001639.3. Note that, based on the comparison between the base sequence of cDNA of a full-length mRNA of human APCS and the base sequence of cDNA of a full-length mRNA of APCS of a non-human species, an antisense-strand nucleic acid and a sense-strand nucleic acid that suppresses expression of APCS mRNA in a non-human species can be designed.

An example of a nucleic acid having APCS expression-suppressing activity is a double-stranded nucleic acid consisting of an antisense-strand nucleic acid of the present invention comprising a complementary base sequence to the APCS mRNA sequence and a sense-strand nucleic acid of the present invention comprising a complementary base sequence to the base sequence of the antisense-strand nucleic acid, and having APCS expression-suppressing activity.

Expression of APCS can be suppressed by introducing the double-stranded nucleic acid of the present invention into a cell. For example, the double-stranded nucleic acid of the present invention is introduced into a cell in a concentration of several pM to several nM and then cultured for 24 hours or more. For example, at the time point of 48 hours after initiation of culture, expression of mRNA of APCS can be suppressed.

The activity to suppress APCS mRNA expression of the double-stranded nucleic acid of the present invention can be evaluated by transfecting e.g., a human cell strain with, e.g., the nucleic acid, by use of, e.g., a cationic liposome, culturing the human cell strain for a predetermined time and thereafter quantifying the expression level of APCS mRNA in the human cell strain.

The activity to suppress APCS mRNA expression of the double-stranded nucleic acid of the present invention can be evaluated by transfecting, e.g., a human cell strain with, e.g., the nucleic acid by use of, e.g., a cationic liposome and culturing for a predetermined time and thereafter quantifying the expression level of APCS mRNA in the human cell strain.

Examples of the nucleic acid having APCS expression-suppressing activity include, other than the above double-stranded nucleic acid, a single-stranded nucleic acid having a base sequence complementary to a part of the base sequence of the APCS mRNA, wherein the single-stranded nucleic acid suppresses expression of APCS. The single-stranded nucleic acid usually consists of 8 to 30 bases, preferably of 12 to 30 bases and more preferably 12 to 20 bases.

An example of the single-stranded nucleic acid is a single-stranded nucleic acid that is the antisense-strand nucleic acid of the double-stranded nucleic acid of the present invention.

Expression of APCS can be suppressed by introducing the antisense-strand nucleic acid of the present invention as a single-stranded nucleic acid into a cell. For example, the single-stranded nucleic acid of the present invention is introduced into a cell in a concentration of several pM to several μM and cultured for 24 hours or more. For example, at the time point of 48 hours after initiation of culture, expression of mRNA of APCS can be suppressed.

The activity to suppress APCS mRNA expression of the antisense-strand nucleic acid of the present invention can be evaluated by transfecting, e.g., a human cell strain with, e.g., the nucleic acid by use of, e.g., a cationic liposome, culturing the human cell strain for a predetermined time and thereafter quantifying the expression level of APCS mRNA in the human cell strain.

3. Pharmaceutical Composition of the Present Invention

The present invention also relates to a pharmaceutical composition comprising a nucleic acid such as a double-stranded nucleic acid and a single-stranded nucleic acid according to the present invention, as an active ingredient. The pharmaceutical composition of the present invention can be used as a therapeutic or prophylactic agent for amyloid-related diseases.

The present invention also provides a method for treating a disorder mediated by APCS-containing amyloid fibrils. In the method of treatment, the nucleic acid of the present invention or the pharmaceutical composition of the present invention is administered to a human in need of such a treatment to successfully treat a disorder mediated by APCS-containing amyloid fibrils.

An example of the disorder mediated by APCS-containing amyloid fibrils is an amyloid-related disease. The double-stranded nucleic acid of the present invention can be used alone in the treatment method; however, the nucleic acid is administered as an active ingredient of the pharmaceutical composition of the present invention to human to successfully produce a medicinal effect, as shown below.

The pharmaceutical composition of the present invention further comprises a carrier effective for allowing the nucleic acid of the present invention to migrate into a cell. Examples of the carrier effective for allowing the nucleic acid to migrate into a cell include a cationic carrier. Examples of the cationic carrier include a cationic liposome and a cationic polymer. As the carrier effective for allowing the nucleic acid to migrate into a cell, a carrier using a virus envelope may be used. Examples of the cationic polymer include JetSI (Qbiogene) and Jet-PEI (polyethyleneimine; Qbiogene). Examples of the carrier using a virus envelope include GenomeOne (HVJ-E liposome; manufactured by Ishihara Sangyo Kaisha, Ltd.).

A pharmaceutical composition comprising the nucleic acid of the present invention and a carrier as mentioned above can be prepared by a method known to those skilled in the art, for example, by mixing an appropriate concentration of a carrier dispersion with a nucleic acid solution. If a cationic carrier is used, since the nucleic acid is usually negatively charged in an aqueous solution, the carrier and the nucleic acid are mixed in an aqueous solution by a routine method to easily and successfully prepare the pharmaceutical composition of the present invention. Examples of the aqueous solvent to be used for preparing a pharmaceutical composition include an electrolyte solution such as water for injection, distilled water for injection and physiological saline; and a sugar solution such as a glucose solution and maltose solution. The conditions such as pH and temperature for preparing the pharmaceutical composition of the present invention can be appropriately selected by those skilled in the art. The pharmaceutical composition is, if necessary, subjected to a dispersion treatment using an ultrasonic disperser or a high pressure emulsifier etc. to obtain a homogeneous composition. Since the optimal method and conditions for preparing a pharmaceutical composition comprising the nucleic acid of the present invention and a carrier vary depending on the carrier to be used, those skilled in the art can select an optimal method depending on the carrier to be used regardless of the above method.

As the pharmaceutical composition of the present invention, for example, composite particles constituted of a nucleic acid and lead particles as components and a composition constituted of composite particles and, if desired, lipid membrane coating the composite particles, can be suitably used. Examples of the lead particles include a lipid assembly, liposomes, emulsion particles, high molecules, metal colloid and a fine particle preparation. Preferably, a liposome is used and more preferably a cationic liposome is used. In the present invention, lead particles may be constituted of a composite of two or more elements selected from, e.g., a lipid assembly, liposomes, emulsion particles, high molecules, metal colloid and a fine particle preparation or a composite constituted of, e.g., a lipid assembly, liposomes, emulsion particles, high molecules, metal colloid and/or a fine particle preparation or another compound (for example, sugar, lipid, and inorganic compound).

Examples of the lipid membrane coating the composite particles include membrane using, e.g., a non-cationic lipid, a lipid inhibiting agglomeration of particles, and a cationic lipid as a constitution component.

The pharmaceutical composition of the present invention can be prepared, for example, in accordance with the method described in International Publication No. WO2006/080118 etc.

With respect to the blending ratio of a nucleic acid and a carrier comprised in the pharmaceutical composition of the present invention, usually 1 to 200 parts by weight of the carrier relative to 1 part by mass of the nucleic acid is appropriate. The blending ratio is preferably 2.5 to 100 parts by mass of a carrier and more preferably 7 to 25 parts by mass of carrier relative to 1 part by mass of the nucleic acid.

The size of the particles constituting the pharmaceutical composition of the present invention in average is preferably about 10 nm to 300 nm, more preferably about 30 nm to 200 nm and further preferably about 50 nm to 150 nm.

The pharmaceutical composition of the present invention may comprise, other than the above carrier, e.g., a pharmaceutically acceptable carrier or a diluent. The pharmaceutically acceptable carrier or diluent is basically a chemically inactive and harmless compound (including a composition) and having no influence on the biological activity of the pharmaceutical composition of the present invention. Examples of the pharmaceutically acceptable carrier or diluent include, but are not particularly limited to, a salt solution, a sugar solution, a glycerol solution and ethanol.

The pharmaceutical composition of the present invention comprises a nucleic acid in an amount effective for treating or preventing a disease and is provided in a form appropriate for administering to patients. Examples of the dosage form of the pharmaceutical composition of the present invention may include a liquid such as an injection, an eye drop and an inhalation; and a topical preparation such as an ointment and a lotion.

In the case of a liquid, the concentration of the nucleic acid of the present invention serving as an active ingredient in the pharmaceutical composition of the present invention usually falls within the range of 0.001 to 25% (w/v), preferably 0.1 to 10% (w/v) and more preferably 0.5 to 5% (w/v). The pharmaceutical composition of the present invention may comprise any pharmaceutically acceptable additives such as an emulsifying aid, a stabilizer, a tonicity agent and/or a pH regulator in appropriate amounts. The pharmaceutically acceptable additives can be added in an appropriate step before and after dispersion of the composite.

The pH of the liquid is usually controlled within the range of about 5.0 to about 8.5 and preferably about 6.0 to about 8.0.

The liquid is preferably subjected to a sterilization treatment such as sterilization by filtration using, e.g., a membrane filter.

The pharmaceutical composition of the present invention can be prepared as a lyophilized preparation. The lyophilized preparation can be prepared by dispersing a nucleic acid and a carrier and lyophilizing the dispersion. The lyophilization can be carried out by a routine method. For example, a predetermined amount of a complex solution dispersed is dispensed in vials in aseptic conditions. The vials are subjected to a pre-drying process at about −40 to −20° C. for about 2 hours, a primary drying process at about 0 to 10° C. under reduced pressure and then a secondary drying process at about 15 to 25° C. under reduced pressure. In this manner, freeze drying can be carried out. Subsequently, the inner atmosphere of the vials is purged with nitrogen gas and a stopper is put on the vials. In this manner, the lyophilized preparation of the pharmaceutical composition of the present invention can be obtained.

The lyophilized preparation can be dissolved again by adding an appropriate solution and put in use. Examples of the solution include water for injection, an electrolyte solution such as and physiological saline; and a glucose solution and other general infusion. The volume of the solution to be used, which varies depending on, e.g., the application. Although it is not particularly limited, the volume is preferably 0.5 to 2 fold as large as the volume before freeze-drying, or 500 mL or less.

The pharmaceutical composition of the present invention can be dosed by intravenous administration, intraarterial administration, oral administration, intra-tissue administration, transdermal administration, transmucosal administration, or rectal administration; however, the composition is preferably dosed by a method appropriate for the symptom of the patient. Particularly intravenous administration, transdermal administration, and transmucosal administration are preferably used. Topical administration such as local administration within, e.g., cancer, can be made. Examples of the dosage form suitable for these administration methods include injections, oral preparations, intravenous fluids, absorbing agents, eye-drops, ointments, lotions and suppositories.

The dose of the pharmaceutical composition of the present invention is desirably determined in consideration of, e.g., the type of drug, dosage form, the state of the patient such as age and body weight; route of administration, and the nature and condition of the disease; however, the dose is usually 0.1 mg to 10 g/day per adult, preferably 1 mg to 500 mg/day per adult, in terms of mass of the nucleic acid. In some cases, the above dose or less is sufficient; on the contrary, the above dose or more is required in other cases. The pharmaceutical composition of the present invention can be administered once to several times at intervals of a single to several days.

EXAMPLES

Now, the present invention will be described by way of Examples; however, the present invention is not limited by these Examples.

Example 1: Synthesis of Double-Stranded Nucleic Acid

Synthesis of sense-strand nucleic acids consisting of the ribonucleotides set forth in SEQ ID NOS: 2 to 644 and antisense-strand nucleic acids consisting of the ribonucleotides set forth in SEQ ID NOS: 645 to 1287 were outsourced to Sigma Aldrich and double-stranded nucleic acids were prepared by annealing them (the sense-strand nucleic acids set forth in SEQ ID NO: n (n=2 to 644) and the antisense-strand nucleic acids set forth in SEQ ID NO: [n+643] are paired).

Example 2: Measurement of APCS mRNA Knockdown Activity

To 384-well culture plates, the double-stranded nucleic acids synthesized in Example 1 and a siRNA/RNAiMax mixture (20 μL) prepared by diluting RNAiMax transfection reagent (manufactured by Thermo Fisher Scientific, catalog number 13778150) with Opti-MEM I Reduced Serum Medium culture medium (manufactured by Thermo Fisher Scientific, catalog number 31985070) were added. A human ovarian cancer-derived cell strain, RMG-I cells (JCRB cell bank, JCRB0172) were seeded so as to be 10,000 cells/40 μL/well to each of the 384-well culture plates and incubated at 37° C. in 5% CO₂ condition for 24 hours. The culture medium used herein was Ham's F-12 Nutrient Mix culture medium (manufactured by Thermo Fisher Scientific, catalog number 11765-047) containing 10% fetal bovine serum (manufactured by Thermo Fisher Scientific, catalog number 10091-148). The final concentration of each of the double-stranded nucleic acids was set at 1 nM. Thereafter, the cells were washed with DPBS (no calcium, no magnesium) (manufactured by Thermo Fisher Scientific, catalog number 14190-144), and then, cDNA was synthesized from each of the plates by TaqMan (registered trademark) Fast Cells-to-CT (trademark) kit (manufactured by Thermo Fisher Scientific, catalog number 4399003) in accordance with the following method. A solution, which was prepared by mixing Lysis solution (contained in the kit) and DNase I (contained in the kit) in a ratio of 100:1, was added by 10 μL for each and the mixture was stirred for 5 minutes. Stop Solution (contained in the kit) was added by 1 μL for each. The mixture was stirred for 2 minutes to obtain an RNA extract. Then, 5 μL of 2×RT Buffer (contained in the kit), 0.5 μL of 20×RT Enzyme Mix (contained in the kit), 2.5 μL of Nuclease-free Water and 2 μL of the RNA extract were mixed. The mixture was allowed to react at 37° C. for 60 minutes and at 95° C. for 5 minutes to synthesize cDNA. The cDNA (2 μL) was added to MicroAmp (registered trademark) EnduraPlate (trademark) Optical 384-Well Clear Reaction Plates with Barcode (manufactured by Thermo Fisher Scientific, catalog number 4483285), and further 5 μL of TaqMan (registered trademark) Fast Universal PCR Master Mix (manufactured by Thermo Fisher Scientific, catalog number 4352042), 2.5 μL of DISTILLED WATER (ULTRAPURE) (manufactured by Thermo Fisher Scientific, catalog number 10977015), 0.25 μL of human APCS probe and 0.25 μL of human ACTB probe were added. Using QuantStudio (trademark) 7 Flex, human APCS gene and human ACTB (actin beta) gene were subjected to real time PCR. The expression level of ACTB as an expressible constituent gene was measured as the internal control and the APCS gene-expression level was corrected. Based on the APCS mRNA amount, which was obtained in the case where RMG-I cells were treated by a transfection reagent alone without using siRNA and specified as 1.0, the relative expression levels of APCS mRNAs of the cells to which individual siRNAs were introduced, were calculated. This experiment was repeated twice. The smallest relative expression levels of APCS mRNAs are shown in Table 1. For convenience sake, Table 1 will be separately shown as follows.

TABLE 1  Double APCS stranded relative nucleic Sense strand sequence Antisense strand  Target APCS  expression acid No. SEQ ID NO: (5′--->3′) SEQ ID NO: sequence (5′--->3′) SEQ ID NO: mRNA sequence level AH0001 SEQ ID NO: 2 GCAUGAAUAUCAGACGCUAGG SEQ ID NO: 645 UAGCGUCUGAUAUUCAUGCCC SEQ ID NO: 1288 GCAUGAAUAUCAGACGCUA 0.305 AH0002 SEQ ID NO: 3 CAUGAAUAUCAGACGCUAGGG SEQ ID NO: 646 CUAGCGUCUGAUAUUCAUGCC SEQ ID NO: 1289 CAUGAAUAUCAGACGCUAG 0.391 AH0003 SEQ ID NO: 4 AUAUCAGACGCUAGGGGGACA SEQ ID NO: 647 UCCCCCUAGCGUCUGAUAUUC SEQ ID NO: 1290 AUAUCAGACGCUAGGGGGA 0.427 AH0004 SEQ ID NO: 5 CUAGGGGGACAGCCACUGUGU SEQ ID NO: 648 ACAGUGGCUGUCCCCCUAGCG SEQ ID NO: 1291 CUAGGGGGACAGCCACUGU 0.405 AH0005 SEQ ID NO: 6 AGGGGGACAGCCACUGUGUUG SEQ ID NO: 649 ACACAGUGGCUGUCCCCCUAG SEQ ID NO: 1292 AGGGGGACAGCCACUGUGU 0.401 AH0006 SEQ ID NO: 7 GGGGACAGCCACUGUGUUGUC SEQ ID NO: 650 CAACACAGUGGCUGUCCCCCU SEQ ID NO: 1293 GGGGACAGCCACUGUGUUG 0.456 AH0007 SEQ ID NO: 8 GGGACAGCCACUGUGUUGUCU SEQ ID NO: 651 ACAACACAGUGGCUGUCCCCC SEQ ID NO: 1294 GGGACAGCCACUGUGUUGU 0.435 AH0008 SEQ ID NO: 9 GGACAGCCACUGUGUUGUCUG SEQ ID NO: 652 GACAACACAGUGGCUGUCCCC SEQ ID NO: 1295 GGACAGCCACUGUGUUGUC 0.436 AH0009 SEQ ID NO: 10 GACAGCCACUGUGUUGUCUGC SEQ ID NO: 653 AGACAACACAGUGGCUGUCCC SEQ ID NO: 1296 GACAGCCACUGUGUUGUCU 0.487 AH0010 SEQ ID NO: 11 GCCACUGUGUUGUCUGCUACC SEQ ID NO: 654 UAGCAGACAACACAGUGGCUG SEQ ID NO: 1297 GCCACUGUGUUGUCUGCUA 0.288 AH0011 SEQ ID NO: 12 CCACUGUGUUGUCUGCUACCC SEQ ID NO: 655 GUAGCAGACAACACAGUGGCU SEQ ID NO: 1298 CCACUGUGUUGUCUGCUAC 0.382 AH0012 SEQ ID NO: 13 CACUGUGUUGUCUGCUACCCU SEQ ID NO: 656 GGUAGCAGACAACACAGUGGC SEQ ID NO: 1299 CACUGUGUUGUCUGCUACC 0.490 AH0013 SEQ ID NO: 14 CUGUGUUGUCUGCUACCCUCA SEQ ID NO: 657 AGGGUAGCAGACAACACAGUG SEQ ID NO: 1300 CUGUGUUGUCUGCUACCCU 0.315 AH0014 SEQ ID NO: 15 UGUGUUGUCUGCUACCCUCAU SEQ ID NO: 658 GAGGGUAGCAGACAACACAGU SEQ ID NO: 1301 UGUGUUGUCUGCUACCCUC 0.360 AH0015 SEQ ID NO: 16 GUGUUGUCUGCUACCCUCAUC SEQ ID NO: 659 UGAGGGUAGCAGACAACACAG SEQ ID NO: 1302 GUGUUGUCUGCUACCCUCA 0.275 AH0016 SEQ ID NO: 17 UGUUGUCUGCUACCCUCAUCC SEQ ID NO: 660 AUGAGGGUAGCAGACAACACA SEQ ID NO: 1303 UGUUGUCUGCUACCCUCAU 0.259 AH0017 SEQ ID NO: 18 GUUGUCUGCUACCCUCAUCCU SEQ ID NO: 661 GAUGAGGGUAGCAGACAACAC SEQ ID NO: 1304 GUUGUCUGCUACCCUCAUC 0.345 AH0018 SEQ ID NO: 19 GUCUGCUACCCUCAUCCUGGU SEQ ID NO: 662 CAGGAUGAGGGUAGCAGACAA SEQ ID NO: 1305 GUCUGCUACCCUCAUCCUG 0.406 AH0019 SEQ ID NO: 20 CUGCUACCCUCAUCCUGGUCA SEQ ID NO: 663 ACCAGGAUGAGGGUAGCAGAC SEQ ID NO: 1306 CUGCUACCCUCAUCCUGGU 0.229 AH0020 SEQ ID NO: 21 GCUACCCUCAUCCUGGUCACU SEQ ID NO: 664 UGACCAGGAUGAGGGUAGCAG SEQ ID NO: 1307 GCUACCCUCAUCCUGGUCA 0.278 AH0021 SEQ ID NO: 22 CUACCCUCAUCCUGGUCACUG SEQ ID NO: 665 GUGACCAGGAUGAGGGUAGCA SEQ ID NO: 1308 CUACCCUCAUCCUGGUCAC 0.284 AH0022 SEQ ID NO: 23 UACCCUCAUCCUGGUCACUGC SEQ ID NO: 666 AGUGACCAGGAUGAGGGUAGC SEQ ID NO: 1309 UACCCUCAUCCUGGUCACU 0.234 AH0023 SEQ ID NO: 24 ACCCUCAUCCUGGUCACUGCU SEQ ID NO: 667 CAGUGACCAGGAUGAGGGUAG SEQ ID NO: 1310 ACCCUCAUCCUGGUCACUG 0.413 AH0024 SEQ ID NO: 25 CCCUCAUCCUGGUCACUGCUU SEQ ID NO: 668 GCAGUGACCAGGAUGAGGGUA SEQ ID NO: 1311 CCCUCAUCCUGGUCACUGC 0.268 AH0025 SEQ ID NO: 26 CCUCAUCCUGGUCACUGCUUC SEQ ID NO: 669 AGCAGUGACCAGGAUGAGGGU SEQ ID NO: 1312 CCUCAUCCUGGUCACUGCU 0.232 AH0026 SEQ ID NO: 27 CUCAUCCUGGUCACUGCUUCU SEQ ID NO: 670 AAGCAGUGACCAGGAUGAGGG SEQ ID NO: 1313 CUCAUCCUGGUCACUGCUU 0.293 AH0027 SEQ ID NO: 28 CAUCCUGGUCACUGCUUCUGC SEQ ID NO: 671 AGAAGCAGUGACCAGGAUGAG SEQ ID NO: 1314 CAUCCUGGUCACUGCUUCU 0.158 AH0028 SEQ ID NO: 29 AUCCUGGUCACUGCUUCUGCU SEQ ID NO: 672 CAGAAGCAGUGACCAGGAUGA SEQ ID NO: 1315 AUCCUGGUCACUGCUUCUG 0.286 AH0029 SEQ ID NO: 30 UCCUGGUCACUGCUUCUGCUA SEQ ID NO: 673 GCAGAAGCAGUGACCAGGAUG SEQ ID NO: 1316 UCCUGGUCACUGCUUCUGC 0.304 AH0030 SEQ ID NO: 31 CCUGGUCACUGCUUCUGCUAU SEQ ID NO: 674 AGCAGAAGCAGUGACCAGGAU SEQ ID NO: 1317 CCUGGUCACUGCUUCUGCU 0.083 AH0031 SEQ ID NO: 32 CUGGUCACUGCUUCUGCUAUA SEQ ID NO: 675 UAGCAGAAGCAGUGACCAGGA SEQ ID NO: 1318 CUGGUCACUGCUUCUGCUA 0.132 AH0032 SEQ ID NO: 33 UGGUCACUGCUUCUGCUAUAA SEQ ID NO: 676 AUAGCAGAAGCAGUGACCAGG SEQ ID NO: 1319 UGGUCACUGCUUCUGCUAU 0.172 AH0033 SEQ ID NO: 34 GGUCACUGCUUCUGCUAUAAC SEQ ID NO: 677 UAUAGCAGAAGCAGUGACCAG SEQ ID NO: 1320 GGUCACUGCUUCUGCUAUA 0.117 AH0034 SEQ ID NO: 35 GUCACUGCUUCUGCUAUAACA SEQ ID NO: 678 UUAUAGCAGAAGCAGUGACCA SEQ ID NO: 1321 GUCACUGCUUCUGCUAUAA 0.174 AH0035 SEQ ID NO: 36 CACUGCUUCUGCUAUAACAGC SEQ ID NO: 679 UGUUAUAGCAGAAGCAGUGAC SEQ ID NO: 1322 CACUGCUUCUGCUAUAACA 0.082 AH0036 SEQ ID NO: 37 ACUGCUUCUGCUAUAACAGCC SEQ ID NO: 680 CUGUUAUAGCAGAAGCAGUGA SEQ ID NO: 1323 ACUGCUUCUGCUAUAACAG 0.215 AH0037 SEQ ID NO: 38 CUGCUUCUGCUAUAACAGCCC SEQ ID NO: 681 GCUGUUAUAGCAGAAGCAGUG SEQ ID NO: 1324 CUGCUUCUGCUAUAACAGC 0.082 AH0038 SEQ ID NO: 39 GCUUCUGCUAUAACAGCCCUA SEQ ID NO: 682 GGGCUGUUAUAGCAGAAGCAG SEQ ID NO: 1325 GCUUCUGCUAUAACAGCCC 0.205 AH0039 SEQ ID NO: 40 CUUCUGCUAUAACAGCCCUAG SEQ ID NO: 683 AGGGCUGUUAUAGCAGAAGCA SEQ ID NO: 1326 CUUCUGCUAUAACAGCCCU 0.165 AH0040 SEQ ID NO: 41 UUCUGCUAUAACAGCCCUAGG SEQ ID NO: 684 UAGGGCUGUUAUAGCAGAAGC SEQ ID NO: 1327 UUCUGCUAUAACAGCCCUA 0.148 AH0041 SEQ ID NO: 42 UCUGCUAUAACAGCCCUAGGC SEQ ID NO: 685 CUAGGGCUGUUAUAGCAGAAG SEQ ID NO: 1328 UCUGCUAUAACAGCCCUAG 0.371 AH0042 SEQ ID NO: 43 CUGCUAUAACAGCCCUAGGCC SEQ ID NO: 686 CCUAGGGCUGUUAUAGCAGAA SEQ ID NO: 1329 CUGCUAUAACAGCCCUAGG 0.203 AH0043 SEQ ID NO: 44 UGCUAUAACAGCCCUAGGCCA SEQ ID NO: 687 GCCUAGGGCUGUUAUAGCAGA SEQ ID NO: 1330 UGCUAUAACAGCCCUAGGC 0.419 AH0044 SEQ ID NO: 45 GCUAUAACAGCCCUAGGCCAG SEQ ID NO: 688 GGCCUAGGGCUGUUAUAGCAG SEQ ID NO: 1331 GCUAUAACAGCCCUAGGCC 0.457 AH0045 SEQ ID NO: 46 CUAUAACAGCCCUAGGCCAGG SEQ ID NO: 689 UGGCCUAGGGCUGUUAUAGCA SEQ ID NO: 1332 CUAUAACAGCCCUAGGCCA 0.115 AH0046 SEQ ID NO: 47 UAUAACAGCCCUAGGCCAGGA SEQ ID NO: 690 CUGGCCUAGGGCUGUUAUAGC SEQ ID NO: 1333 UAUAACAGCCCUAGGCCAG 0.300 AH0047 SEQ ID NO: 48 AUAACAGCCCUAGGCCAGGAA SEQ ID NO: 691 CCUGGCCUAGGGCUGUUAUAG SEQ ID NO: 1334 AUAACAGCCCUAGGCCAGG 0.396 AH0048 SEQ ID NO: 49 UAACAGCCCUAGGCCAGGAAU SEQ ID NO: 692 UCCUGGCCUAGGGCUGUUAUA SEQ ID NO: 1335 UAACAGCCCUAGGCCAGGA 0.479 AH0049 SEQ ID NO: 50 ACAGCCCUAGGCCAGGAAUAU SEQ ID NO: 693 AUUCCUGGCCUAGGGCUGUUA SEQ ID NO: 1336 ACAGCCCUAGGCCAGGAAU 0.283 AH0050 SEQ ID NO: 51 CAGCCCUAGGCCAGGAAUAUG SEQ ID NO: 694 UAUUCCUGGCCUAGGGCUGUU SEQ ID NO: 1337 CAGCCCUAGGCCAGGAAUA 0.293 AH0051 SEQ ID NO: 52 AGCCCUAGGCCAGGAAUAUGA SEQ ID NO: 695 AUAUUCCUGGCCUAGGGCUGU SEQ ID NO: 1338 AGCCCUAGGCCAGGAAUAU 0.220 AH0052 SEQ ID NO: 53 GCCCUAGGCCAGGAAUAUGAA SEQ ID NO: 696 CAUAUUCCUGGCCUAGGGCUG SEQ ID NO: 1339 GCCCUAGGCCAGGAAUAUG 0.189 AH0053 SEQ ID NO: 54 CCCUAGGCCAGGAAUAUGAAC SEQ ID NO: 697 UCAUAUUCCUGGCCUAGGGCU SEQ ID NO: 1340 CCCUAGGCCAGGAAUAUGA 0.158 AH0054 SEQ ID NO: 55 CCUAGGCCAGGAAUAUGAACA SEQ ID NO: 698 UUCAUAUUCCUGGCCUAGGGC SEQ ID NO: 1341 CCUAGGCCAGGAAUAUGAA 0.188 AH0055 SEQ ID NO: 56 CUAGGCCAGGAAUAUGAACAA SEQ ID NO: 699 GUUCAUAUUCCUGGCCUAGGG SEQ ID NO: 1342 CUAGGCCAGGAAUAUGAAC 0.433 AH0056 SEQ ID NO: 57 UAGGCCAGGAAUAUGAACAAG SEQ ID NO: 700 UGUUCAUAUUCCUGGCCUAGG SEQ ID NO: 1343 UAGGCCAGGAAUAUGAACA 0.242 AH0057 SEQ ID NO: 58 AGGCCAGGAAUAUGAACAAGC SEQ ID NO: 701 UUGUUCAUAUUCCUGGCCUAG SEQ ID NO: 1344 AGGCCAGGAAUAUGAACAA 0.107 AH0058 SEQ ID NO: 59 GGCCAGGAAUAUGAACAAGCC SEQ ID NO: 702 CUUGUUCAUAUUCCUGGCCUA SEQ ID NO: 1345 GGCCAGGAAUAUGAACAAG 0.428 AH0059 SEQ ID NO: 60 GCCAGGAAUAUGAACAAGCCG SEQ ID NO: 703 GCUUGUUCAUAUUCCUGGCCU SEQ ID NO: 1346 GCCAGGAAUAUGAACAAGC 0.221 AH0060 SEQ ID NO: 61 CCAGGAAUAUGAACAAGCCGC SEQ ID NO: 704 GGCUUGUUCAUAUUCCUGGCC SEQ ID NO: 1347 CCAGGAAUAUGAACAAGCC 0.242 AH0061 SEQ ID NO: 62 CAGGAAUAUGAACAAGCCGCU SEQ ID NO: 705 CGGCUUGUUCAUAUUCCUGGC SEQ ID NO: 1348 CAGGAAUAUGAACAAGCCG 0.299 AH0062 SEQ ID NO: 63 AGGAAUAUGAACAAGCCGCUG SEQ ID NO: 706 GCGGCUUGUUCAUAUUCCUGG SEQ ID NO: 1349 AGGAAUAUGAACAAGCCGC 0.309 AH0063 SEQ ID NO: 64 GGAAUAUGAACAAGCCGCUGC SEQ ID NO: 707 AGCGGCUUGUUCAUAUUCCUG SEQ ID NO: 1350 GGAAUAUGAACAAGCCGCU 0.113 AH0064 SEQ ID NO: 65 GAAUAUGAACAAGCCGCUGCU SEQ ID NO: 708 CAGCGGCUUGUUCAUAUUCCU SEQ ID NO: 1351 GAAUAUGAACAAGCCGCUG 0.103 AH0065 SEQ ID NO: 66 AAUAUGAACAAGCCGCUGCUU SEQ ID NO: 709 GCAGCGGCUUGUUCAUAUUCC SEQ ID NO: 1352 AAUAUGAACAAGCCGCUGC 0.444 AH0066 SEQ ID NO: 67 AUAUGAACAAGCCGCUGCUUU SEQ ID NO: 710 AGCAGCGGCUUGUUCAUAUUC SEQ ID NO: 1353 AUAUGAACAAGCCGCUGCU 0.198 AH0067 SEQ ID NO: 68 UAUGAACAAGCCGCUGCUUUG SEQ ID NO: 711 AAGCAGCGGCUUGUUCAUAUU SEQ ID NO: 1354 UAUGAACAAGCCGCUGCUU 0.464 AH0068 SEQ ID NO: 69 AUGAACAAGCCGCUGCUUUGG SEQ ID NO: 712 AAAGCAGCGGCUUGUUCAUAU SEQ ID NO: 1355 AUGAACAAGCCGCUGCUUU 0.190 AH0069 SEQ ID NO: 70 UGAACAAGCCGCUGCUUUGGA SEQ ID NO: 713 CAAAGCAGCGGCUUGUUCAUA SEQ ID NO: 1356 UGAACAAGCCGCUGCUUUG 0.150 AH0070 SEQ ID NO: 71 GAACAAGCCGCUGCUUUGGAU SEQ ID NO: 714 CCAAAGCAGCGGCUUGUUCAU SEQ ID NO: 1357 GAACAAGCCGCUGCUUUGG 0.149 AH0071 SEQ ID NO: 72 AACAAGCCGCUGCUUUGGAUC SEQ ID NO: 715 UCCAAAGCAGCGGCUUGUUCA SEQ ID NO: 1358 AACAAGCCGCUGCUUUGGA 0.180 AH0072 SEQ ID NO: 73 ACAAGCCGCUGCUUUGGAUCU SEQ ID NO: 716 AUCCAAAGCAGCGGCUUGUUC SEQ ID NO: 1359 ACAAGCCGCUGCUUUGGAU 0.078 AH0073 SEQ ID NO: 74 CAAGCCGCUGCUUUGGAUCUC SEQ ID NO: 717 GAUCCAAAGCAGCGGCUUGUU SEQ ID NO: 1360 CAAGCCGCUGCUUUGGAUC 0.100 AH0074 SEQ ID NO: 75 AAGCCGCUGCUUUGGAUCUCU SEQ ID NO: 718 AGAUCCAAAGCAGCGGCUUGU SEQ ID NO: 1361 AAGCCGCUGCUUUGGAUCU 0.127 AH0075 SEQ ID NO: 76 AGCCGCUGCUUUGGAUCUCUG SEQ ID NO: 719 GAGAUCCAAAGCAGCGGCUUG SEQ ID NO: 1362 AGCCGCUGCUUUGGAUCUC 0.123 AH0076 SEQ ID NO: 77 GCCGCUGCUUUGGAUCUCUGU SEQ ID NO: 720 AGAGAUCCAAAGCAGCGGCUU SEQ ID NO: 1363 GCCGCUGCUUUGGAUCUCU 0.047 AH0077 SEQ ID NO: 78 CCGCUGCUUUGGAUCUCUGUC SEQ ID NO: 721 CAGAGAUCCAAAGCAGCGGCU SEQ ID NO: 1364 CCGCUGCUUUGGAUCUCUG 0.054 AH0078 SEQ ID NO: 79 CGCUGCUUUGGAUCUCUGUCC SEQ ID NO: 722 ACAGAGAUCCAAAGCAGCGGC SEQ ID NO: 1365 CGCUGCUUUGGAUCUCUGU 0.064 AH0079 SEQ ID NO: 80 GCUGCUUUGGAUCUCUGUCCU SEQ ID NO: 723 GACAGAGAUCCAAAGCAGCGG SEQ ID NO: 1366 GCUGCUUUGGAUCUCUGUC 0.090 AH0080 SEQ ID NO: 81 CUGCUUUGGAUCUCUGUCCUC SEQ ID NO: 724 GGACAGAGAUCCAAAGCAGCG SEQ ID NO: 1367 CUGCUUUGGAUCUCUGUCC 0.296 AH0081 SEQ ID NO: 82 UGCUUUGGAUCUCUGUCCUCA SEQ ID NO: 725 AGGACAGAGAUCCAAAGCAGC SEQ ID NO: 1368 UGCUUUGGAUCUCUGUCCU 0.088 AH0082 SEQ ID NO: 83 GCUUUGGAUCUCUGUCCUCAC SEQ ID NO: 726 GAGGACAGAGAUCCAAAGCAG SEQ ID NO: 1369 GCUUUGGAUCUCUGUCCUC 0.131 AH0083 SEQ ID NO: 84 CUUUGGAUCUCUGUCCUCACC SEQ ID NO: 727 UGAGGACAGAGAUCCAAAGCA SEQ ID NO: 1370 CUUUGGAUCUCUGUCCUCA 0.070 AH0084 SEQ ID NO: 85 UUUGGAUCUCUGUCCUCACCA SEQ ID NO: 728 GUGAGGACAGAGAUCCAAAGC SEQ ID NO: 1371 UUUGGAUCUCUGUCCUCAC 0.300 AH0085 SEQ ID NO: 86 GGAUCUCUGUCCUCACCAGCC SEQ ID NO: 729 CUGGUGAGGACAGAGAUCCAA SEQ ID NO: 1372 GGAUCUCUGUCCUCACCAG 0.129 AH0086 SEQ ID NO: 87 GAUCUCUGUCCUCACCAGCCU SEQ ID NO: 730 GCUGGUGAGGACAGAGAUCCA SEQ ID NO: 1373 GAUCUCUGUCCUCACCAGC 0.483 AH0087 SEQ ID NO: 88 CUCUGUCCUCACCAGCCUCCU SEQ ID NO: 731 GAGGCUGGUGAGGACAGAGAU SEQ ID NO: 1374 CUCUGUCCUCACCAGCCUC 0.263 AH0088 SEQ ID NO: 89 CUGUCCUCACCAGCCUCCUGG SEQ ID NO: 732 AGGAGGCUGGUGAGGACAGAG SEQ ID NO: 1375 CUGUCCUCACCAGCCUCCU 0.413 AH0089 SEQ ID NO: 90 UGUCCUCACCAGCCUCCUGGA SEQ ID NO: 733 CAGGAGGCUGGUGAGGACAGA SEQ ID NO: 1376 UGUCCUCACCAGCCUCCUG 0.334 AH0090 SEQ ID NO: 91 GUCCUCACCAGCCUCCUGGAA SEQ ID NO: 734 CCAGGAGGCUGGUGAGGACAG SEQ ID NO: 1377 GUCCUCACCAGCCUCCUGG 0.295 AH0091 SEQ ID NO: 92 UCCUCACCAGCCUCCUGGAAG SEQ ID NO: 735 UCCAGGAGGCUGGUGAGGACA SEQ ID NO: 1378 UCCUCACCAGCCUCCUGGA 0.300 AH0092 SEQ ID NO: 93 CUCACCAGCCUCCUGGAAGCC SEQ ID NO: 736 CUUCCAGGAGGCUGGUGAGGA SEQ ID NO: 1379 CUCACCAGCCUCCUGGAAG 0.243 AH0093 SEQ ID NO: 94 UCACCAGCCUCCUGGAAGCCU SEQ ID NO: 737 GCUUCCAGGAGGCUGGUGAGG SEQ ID NO: 1380 UCACCAGCCUCCUGGAAGC 0.286 AH0094 SEQ ID NO: 95 ACCAGCCUCCUGGAAGCCUUU SEQ ID NO: 738 AGGCUUCCAGGAGGCUGGUGA SEQ ID NO: 1381 ACCAGCCUCCUGGAAGCCU 0.365 AH0095 SEQ ID NO: 96 CCAGCCUCCUGGAAGCCUUUG SEQ ID NO: 739 AAGGCUUCCAGGAGGCUGGUG SEQ ID NO: 1382 CCAGCCUCCUGGAAGCCUU 0.060 AH0096 SEQ ID NO: 97 CAGCCUCCUGGAAGCCUUUGC SEQ ID NO: 740 AAAGGCUUCCAGGAGGCUGGU SEQ ID NO: 1383 CAGCCUCCUGGAAGCCUUU 0.066 AH0097 SEQ ID NO: 98 AGCCUCCUGGAAGCCUUUGCU SEQ ID NO: 741 CAAAGGCUUCCAGGAGGCUGG SEQ ID NO: 1384 AGCCUCCUGGAAGCCUUUG 0.486 AH0098 SEQ ID NO: 99 GCCUCCUGGAAGCCUUUGCUC SEQ ID NO: 742 GCAAAGGCUUCCAGGAGGCUG SEQ ID NO: 1385 GCCUCCUGGAAGCCUUUGC 0.374 AH0099 SEQ ID NO: 100 CCUCCUGGAAGCCUUUGCUCA SEQ ID NO: 743 AGCAAAGGCUUCCAGGAGGCU SEQ ID NO: 1386 CCUCCUGGAAGCCUUUGCU 0.111 AH0100 SEQ ID NO: 101 CUCCUGGAAGCCUUUGCUCAC SEQ ID NO: 744 GAGCAAAGGCUUCCAGGAGGC SEQ ID NO: 1387 CUCCUGGAAGCCUUUGCUC 0.310 AH0101 SEQ ID NO: 102 UCCUGGAAGCCUUUGCUCACA SEQ ID NO: 745 UGAGCAAAGGCUUCCAGGAGG SEQ ID NO: 1388 UCCUGGAAGCCUUUGCUCA 0.053 AH0102 SEQ ID NO: 103 CCUGGAAGCCUUUGCUCACAC SEQ ID NO: 746 GUGAGCAAAGGCUUCCAGGAG SEQ ID NO: 1389 CCUGGAAGCCUUUGCUCAC 0.086 AH0103 SEQ ID NO: 104 CUGGAAGCCUUUGCUCACACA SEQ ID NO: 747 UGUGAGCAAAGGCUUCCAGGA SEQ ID NO: 1390 CUGGAAGCCUUUGCUCACA 0.121 AH0104 SEQ ID NO: 105 GGAAGCCUUUGCUCACACAGA SEQ ID NO: 748 UGUGUGAGCAAAGGCUUCCAG SEQ ID NO: 1391 GGAAGCCUUUGCUCACACA 0.161 AH0105 SEQ ID NO: 106 GAAGCCUUUGCUCACACAGAC SEQ ID NO: 749 CUGUGUGAGCAAAGGCUUCCA SEQ ID NO: 1392 GAAGCCUUUGCUCACACAG 0.291 AH0106 SEQ ID NO: 107 AAGCCUUUGCUCACACAGACC SEQ ID NO: 750 UCUGUGUGAGCAAAGGCUUCC SEQ ID NO: 1393 AAGCCUUUGCUCACACAGA 0.065 AH0107 SEQ ID NO: 108 AGCCUUUGCUCACACAGACCU SEQ ID NO: 751 GUCUGUGUGAGCAAAGGCUUC SEQ ID NO: 1394 AGCCUUUGCUCACACAGAC 0.136 AH0108 SEQ ID NO: 109 GCCUUUGCUCACACAGACCUC SEQ ID NO: 752 GGUCUGUGUGAGCAAAGGCUU SEQ ID NO: 1395 GCCUUUGCUCACACAGACC 0.094 AH0109 SEQ ID NO: 110 CCUUUGCUCACACAGACCUCA SEQ ID NO: 753 AGGUCUGUGUGAGCAAAGGCU SEQ ID NO: 1396 CCUUUGCUCACACAGACCU 0.107 AH0110 SEQ ID NO: 111 CUUUGCUCACACAGACCUCAG SEQ ID NO: 754 GAGGUCUGUGUGAGCAAAGGC SEQ ID NO: 1397 CUUUGCUCACACAGACCUC 0.254 AH0111 SEQ ID NO: 112 UUUGCUCACACAGACCUCAGU SEQ ID NO: 755 UGAGGUCUGUGUGAGCAAAGG SEQ ID NO: 1398 UUUGCUCACACAGACCUCA 0.334 AH0112 SEQ ID NO: 113 UGCUCACACAGACCUCAGUGG SEQ ID NO: 756 ACUGAGGUCUGUGUGAGCAAA SEQ ID NO: 1399 UGCUCACACAGACCUCAGU 0.302 AH0113 SEQ ID NO: 114 CUCACACAGACCUCAGUGGGA SEQ ID NO: 757 CCACUGAGGUCUGUGUGAGCA SEQ ID NO: 1400 CUCACACAGACCUCAGUGG 0.490 AH0114 SEQ ID NO: 115 CACACAGACCUCAGUGGGAAG SEQ ID NO: 758 UCCCACUGAGGUCUGUGUGAG SEQ ID NO: 1401 CACACAGACCUCAGUGGGA 0.109 AH0115 SEQ ID NO: 116 ACACAGACCUCAGUGGGAAGG SEQ ID NO: 759 UUCCCACUGAGGUCUGUGUGA SEQ ID NO: 1402 ACACAGACCUCAGUGGGAA 0.105 AH0116 SEQ ID NO: 117 CACAGACCUCAGUGGGAAGGU SEQ ID NO: 760 CUUCCCACUGAGGUCUGUGUG SEQ ID NO: 1403 CACAGACCUCAGUGGGAAG 0.478 AH0117 SEQ ID NO: 118 AGACCUCAGUGGGAAGGUGUU SEQ ID NO: 761 CACCUUCCCACUGAGGUCUGU SEQ ID NO: 1404 AGACCUCAGUGGGAAGGUG 0.157 AH0118 SEQ ID NO: 119 GACCUCAGUGGGAAGGUGUUU SEQ ID NO: 762 ACACCUUCCCACUGAGGUCUG SEQ ID NO: 1405 GACCUCAGUGGGAAGGUGU 0.149 AH0119 SEQ ID NO: 120 ACCUCAGUGGGAAGGUGUUUG SEQ ID NO: 763 AACACCUUCCCACUGAGGUCU SEQ ID NO: 1406 ACCUCAGUGGGAAGGUGUU 0.123 AH0120 SEQ ID NO: 121 CCUCAGUGGGAAGGUGUUUGU SEQ ID NO: 764 AAACACCUUCCCACUGAGGUC SEQ ID NO: 1407 CCUCAGUGGGAAGGUGUUU 0.261 AH0121 SEQ ID NO: 122 CUCAGUGGGAAGGUGUUUGUA SEQ ID NO: 765 CAAACACCUUCCCACUGAGGU SEQ ID NO: 1408 CUCAGUGGGAAGGUGUUUG 0.316 AH0122 SEQ ID NO: 123 UCAGUGGGAAGGUGUUUGUAU SEQ ID NO: 766 ACAAACACCUUCCCACUGAGG SEQ ID NO: 1409 UCAGUGGGAAGGUGUUUGU 0.125 AH0123 SEQ ID NO: 124 CAGUGGGAAGGUGUUUGUAUU SEQ ID NO: 767 UACAAACACCUUCCCACUGAG SEQ ID NO: 1410 CAGUGGGAAGGUGUUUGUA 0.185 AH0124 SEQ ID NO: 125 AGUGGGAAGGUGUUUGUAUUU SEQ ID NO: 768 AUACAAACACCUUCCCACUGA SEQ ID NO: 1411 AGUGGGAAGGUGUUUGUAU 0.105 AH0125 SEQ ID NO: 126 GUGGGAAGGUGUUUGUAUUUC SEQ ID NO: 769 AAUACAAACACCUUCCCACUG SEQ ID NO: 1412 GUGGGAAGGUGUUUGUAUU 0.101 AH0126 SEQ ID NO: 127 UGGGAAGGUGUUUGUAUUUCC SEQ ID NO: 770 AAAUACAAACACCUUCCCACU SEQ ID NO: 1413 UGGGAAGGUGUUUGUAUUU 0.150 AH0127 SEQ ID NO: 128 GGGAAGGUGUUUGUAUUUCCU SEQ ID NO: 771 GAAAUACAAACACCUUCCCAC SEQ ID NO: 1414 GGGAAGGUGUUUGUAUUUC 0.386 AH0128 SEQ ID NO: 129 GGAAGGUGUUUGUAUUUCCUA SEQ ID NO: 772 GGAAAUACAAACACCUUCCCA SEQ ID NO: 1415 GGAAGGUGUUUGUAUUUCC 0.127 AH0129 SEQ ID NO: 130 GAAGGUGUUUGUAUUUCCUAG SEQ ID NO: 773 AGGAAAUACAAACACCUUCCC SEQ ID NO: 1416 GAAGGUGUUUGUAUUUCCU 0.077 AH0130 SEQ ID NO: 131 AAGGUGUUUGUAUUUCCUAGA SEQ ID NO: 774 UAGGAAAUACAAACACCUUCC SEQ ID NO: 1417 AAGGUGUUUGUAUUUCCUA 0.213 AH0131 SEQ ID NO: 132 AGGUGUUUGUAUUUCCUAGAG SEQ ID NO: 775 CUAGGAAAUACAAACACCUUC SEQ ID NO: 1418 AGGUGUUUGUAUUUCCUAG 0.084 AH0132 SEQ ID NO: 133 GGUGUUUGUAUUUCCUAGAGA SEQ ID NO: 776 UCUAGGAAAUACAAACACCUU SEQ ID NO: 1419 GGUGUUUGUAUUUCCUAGA 0.112 AH0133 SEQ ID NO: 134 GUGUUUGUAUUUCCUAGAGAA SEQ ID NO: 777 CUCUAGGAAAUACAAACACCU SEQ ID NO: 1420 GUGUUUGUAUUUCCUAGAG 0.153 AH0134 SEQ ID NO: 135 UGUUUGUAUUUCCUAGAGAAU SEQ ID NO: 778 UCUCUAGGAAAUACAAACACC SEQ ID NO: 1421 UGUUUGUAUUUCCUAGAGA 0.139 AH0135 SEQ ID NO: 136 GUUUGUAUUUCCUAGAGAAUC SEQ ID NO: 779 UUCUCUAGGAAAUACAAACAC SEQ ID NO: 1422 GUUUGUAUUUCCUAGAGAA 0.070 AH0136 SEQ ID NO: 137 UUUGUAUUUCCUAGAGAAUCU SEQ ID NO: 780 AUUCUCUAGGAAAUACAAACA SEQ ID NO: 1423 UUUGUAUUUCCUAGAGAAU 0.125 AH0137 SEQ ID NO: 138 UUGUAUUUCCUAGAGAAUCUG SEQ ID NO: 781 GAUUCUCUAGGAAAUACAAAC SEQ ID NO: 1424 UUGUAUUUCCUAGAGAAUC 0.451 AH0138 SEQ ID NO: 139 UGUAUUUCCUAGAGAAUCUGU SEQ ID NO: 782 AGAUUCUCUAGGAAAUACAAA SEQ ID NO: 1425 UGUAUUUCCUAGAGAAUCU 0.204 AH0139 SEQ ID NO: 140 GUAUUUCCUAGAGAAUCUGUU SEQ ID NO: 783 CAGAUUCUCUAGGAAAUACAA SEQ ID NO: 1426 GUAUUUCCUAGAGAAUCUG 0.071 AH0140 SEQ ID NO: 141 UAUUUCCUAGAGAAUCUGUUA SEQ ID NO: 784 ACAGAUUCUCUAGGAAAUACA SEQ ID NO: 1427 UAUUUCCUAGAGAAUCUGU 0.242 AH0141 SEQ ID NO: 142 AUUUCCUAGAGAAUCUGUUAC SEQ ID NO: 785 AACAGAUUCUCUAGGAAAUAC SEQ ID NO: 1428 AUUUCCUAGAGAAUCUGUU 0.123 AH0142 SEQ ID NO: 143 UUUCCUAGAGAAUCUGUUACU SEQ ID NO: 786 UAACAGAUUCUCUAGGAAAUA SEQ ID NO: 1429 UUUCCUAGAGAAUCUGUUA 0.179 AH0143 SEQ ID NO: 144 UCCUAGAGAAUCUGUUACUGA SEQ ID NO: 787 AGUAACAGAUUCUCUAGGAAA SEQ ID NO: 1430 UCCUAGAGAAUCUGUUACU 0.311 AH0144 SEQ ID NO: 145 CCUAGAGAAUCUGUUACUGAU SEQ ID NO: 788 CAGUAACAGAUUCUCUAGGAA SEQ ID NO: 1431 CCUAGAGAAUCUGUUACUG 0.137 AH0145 SEQ ID NO: 146 CUAGAGAAUCUGUUACUGAUC SEQ ID NO: 789 UCAGUAACAGAUUCUCUAGGA SEQ ID NO: 1432 CUAGAGAAUCUGUUACUGA 0.039 AH0146 SEQ ID NO: 147 UAGAGAAUCUGUUACUGAUCA SEQ ID NO: 790 AUCAGUAACAGAUUCUCUAGG SEQ ID NO: 1433 UAGAGAAUCUGUUACUGAU 0.051 AH0147 SEQ ID NO: 148 AGAGAAUCUGUUACUGAUCAU SEQ ID NO: 791 GAUCAGUAACAGAUUCUCUAG SEQ ID NO: 1434 AGAGAAUCUGUUACUGAUC 0.361 AH0148 SEQ ID NO: 149 GAGAAUCUGUUACUGAUCAUG SEQ ID NO: 792 UGAUCAGUAACAGAUUCUCUA SEQ ID NO: 1435 GAGAAUCUGUUACUGAUCA 0.090 AH0149 SEQ ID NO: 150 AGAAUCUGUUACUGAUCAUGU SEQ ID NO: 793 AUGAUCAGUAACAGAUUCUCU SEQ ID NO: 1436 AGAAUCUGUUACUGAUCAU 0.211 AH0150 SEQ ID NO: 151 GAAUCUGUUACUGAUCAUGUA SEQ ID NO: 794 CAUGAUCAGUAACAGAUUCUC SEQ ID NO: 1437 GAAUCUGUUACUGAUCAUG 0.183 AH0151 SEQ ID NO: 152 AAUCUGUUACUGAUCAUGUAA SEQ ID NO: 795 ACAUGAUCAGUAACAGAUUCU SEQ ID NO: 1438 AAUCUGUUACUGAUCAUGU 0.477 AH0152 SEQ ID NO: 153 AUCUGUUACUGAUCAUGUAAA SEQ ID NO: 796 UACAUGAUCAGUAACAGAUUC SEQ ID NO: 1439 AUCUGUUACUGAUCAUGUA 0.103 AH0153 SEQ ID NO: 154 UCUGUUACUGAUCAUGUAAAC SEQ ID NO: 797 UUACAUGAUCAGUAACAGAUU SEQ ID NO: 1440 UCUGUUACUGAUCAUGUAA 0.166 AH0154 SEQ ID NO: 155 CUGUUACUGAUCAUGUAAACU SEQ ID NO: 798 UUUACAUGAUCAGUAACAGAU SEQ ID NO: 1441 CUGUUACUGAUCAUGUAAA 0.155 AH0155 SEQ ID NO: 156 UGUUACUGAUCAUGUAAACUU SEQ ID NO: 799 GUUUACAUGAUCAGUAACAGA SEQ ID NO: 1442 UGUUACUGAUCAUGUAAAC 0.260 AH0156 SEQ ID NO: 157 GUUACUGAUCAUGUAAACUUG SEQ ID NO: 800 AGUUUACAUGAUCAGUAACAG SEQ ID NO: 1443 GUUACUGAUCAUGUAAACU 0.213 AH0157 SEQ ID NO: 158 ACUGAUCAUGUAAACUUGAUC SEQ ID NO: 801 UCAAGUUUACAUGAUCAGUAA SEQ ID NO: 1444 ACUGAUCAUGUAAACUUGA 0.365 AH0158 SEQ ID NO: 159 CUGAUCAUGUAAACUUGAUCA SEQ ID NO: 802 AUCAAGUUUACAUGAUCAGUA SEQ ID NO: 1445 CUGAUCAUGUAAACUUGAU 0.167 AH0159 SEQ ID NO: 160 UGAUCAUGUAAACUUGAUCAC SEQ ID NO: 803 GAUCAAGUUUACAUGAUCAGU SEQ ID NO: 1446 UGAUCAUGUAAACUUGAUC 0.457 AH0160 SEQ ID NO: 161 GAUCAUGUAAACUUGAUCACA SEQ ID NO: 804 UGAUCAAGUUUACAUGAUCAG SEQ ID NO: 1447 GAUCAUGUAAACUUGAUCA 0.338 AH0161 SEQ ID NO: 162 UCAUGUAAACUUGAUCACACC SEQ ID NO: 805 UGUGAUCAAGUUUACAUGAUC SEQ ID NO: 1448 UCAUGUAAACUUGAUCACA 0.286 AH0162 SEQ ID NO: 163 CAUGUAAACUUGAUCACACCG SEQ ID NO: 806 GUGUGAUCAAGUUUACAUGAU SEQ ID NO: 1449 CAUGUAAACUUGAUCACAC 0.485 AH0163 SEQ ID NO: 164 UAAACUUGAUCACACCGCUGG SEQ ID NO: 807 AGCGGUGUGAUCAAGUUUACA SEQ ID NO: 1450 UAAACUUGAUCACACCGCU 0.355 AH0164 SEQ ID NO: 165 AAACUUGAUCACACCGCUGGA SEQ ID NO: 808 CAGCGGUGUGAUCAAGUUUAC SEQ ID NO: 1451 AAACUUGAUCACACCGCUG 0.360 AH0165 SEQ ID NO: 166 ACUUGAUCACACCGCUGGAGA SEQ ID NO: 809 UCCAGCGGUGUGAUCAAGUUU SEQ ID NO: 1452 ACUUGAUCACACCGCUGGA 0.212 AH0166 SEQ ID NO: 167 UUGAUCACACCGCUGGAGAAG SEQ ID NO: 810 UCUCCAGCGGUGUGAUCAAGU SEQ ID NO: 1453 UUGAUCACACCGCUGGAGA 0.493 AH0167 SEQ ID NO: 168 UGAUCACACCGCUGGAGAAGC SEQ ID NO: 811 UUCUCCAGCGGUGUGAUCAAG SEQ ID NO: 1454 UGAUCACACCGCUGGAGAA 0.078 AH0168 SEQ ID NO: 169 GAUCACACCGCUGGAGAAGCC SEQ ID NO: 812 CUUCUCCAGCGGUGUGAUCAA SEQ ID NO: 1455 GAUCACACCGCUGGAGAAG 0.465 AH0169 SEQ ID NO: 170 CACACCGCUGGAGAAGCCUCU SEQ ID NO: 813 AGGCUUCUCCAGCGGUGUGAU SEQ ID NO: 1456 CACACCGCUGGAGAAGCCU 0.312 AH0170 SEQ ID NO: 171 ACACCGCUGGAGAAGCCUCUA SEQ ID NO: 814 GAGGCUUCUCCAGCGGUGUGA SEQ ID NO: 1457 ACACCGCUGGAGAAGCCUC 0.208 AH0171 SEQ ID NO: 172 CACCGCUGGAGAAGCCUCUAC SEQ ID NO: 815 AGAGGCUUCUCCAGCGGUGUG SEQ ID NO: 1458 CACCGCUGGAGAAGCCUCU 0.190 AH0172 SEQ ID NO: 173 ACCGCUGGAGAAGCCUCUACA SEQ ID NO: 816 UAGAGGCUUCUCCAGCGGUGU SEQ ID NO: 1459 ACCGCUGGAGAAGCCUCUA 0.276 AH0173 SEQ ID NO: 174 CCGCUGGAGAAGCCUCUACAG SEQ ID NO: 817 GUAGAGGCUUCUCCAGCGGUG SEQ ID NO: 1460 CCGCUGGAGAAGCCUCUAC 0.397 AH0174 SEQ ID NO: 175 CGCUGGAGAAGCCUCUACAGA SEQ ID NO: 818 UGUAGAGGCUUCUCCAGCGGU SEQ ID NO: 1461 CGCUGGAGAAGCCUCUACA 0.056 AH0175 SEQ ID NO: 176 GCUGGAGAAGCCUCUACAGAA SEQ ID NO: 819 CUGUAGAGGCUUCUCCAGCGG SEQ ID NO: 1462 GCUGGAGAAGCCUCUACAG 0.335 AH0176 SEQ ID NO: 177 CUGGAGAAGCCUCUACAGAAC SEQ ID NO: 820 UCUGUAGAGGCUUCUCCAGCG SEQ ID NO: 1463 CUGGAGAAGCCUCUACAGA 0.080 AH0177 SEQ ID NO: 178 UGGAGAAGCCUCUACAGAACU SEQ ID NO: 821 UUCUGUAGAGGCUUCUCCAGC SEQ ID NO: 1464 UGGAGAAGCCUCUACAGAA 0.088 AH0178 SEQ ID NO: 179 GGAGAAGCCUCUACAGAACUU SEQ ID NO: 822 GUUCUGUAGAGGCUUCUCCAG SEQ ID NO: 1465 GGAGAAGCCUCUACAGAAC 0.142 AH0179 SEQ ID NO: 180 GAGAAGCCUCUACAGAACUUU SEQ ID NO: 823 AGUUCUGUAGAGGCUUCUCCA SEQ ID NO: 1466 GAGAAGCCUCUACAGAACU 0.276 AH0180 SEQ ID NO: 181 AGAAGCCUCUACAGAACUUUA SEQ ID NO: 824 AAGUUCUGUAGAGGCUUCUCC SEQ ID NO: 1467 AGAAGCCUCUACAGAACUU 0.160 AH0181 SEQ ID NO: 182 GAAGCCUCUACAGAACUUUAC SEQ ID NO: 825 AAAGUUCUGUAGAGGCUUCUC SEQ ID NO: 1468 GAAGCCUCUACAGAACUUU 0.156 AH0182 SEQ ID NO: 183 AAGCCUCUACAGAACUUUACC SEQ ID NO: 826 UAAAGUUCUGUAGAGGCUUCU SEQ ID NO: 1469 AAGCCUCUACAGAACUUUA 0.210 AH0183 SEQ ID NO: 184 AGCCUCUACAGAACUUUACCU SEQ ID NO: 827 GUAAAGUUCUGUAGAGGCUUC SEQ ID NO: 1470 AGCCUCUACAGAACUUUAC 0.305 AH0184 SEQ ID NO: 185 GCCUCUACAGAACUUUACCUU SEQ ID NO: 828 GGUAAAGUUCUGUAGAGGCUU SEQ ID NO: 1471 GCCUCUACAGAACUUUACC 0.343 AH0185 SEQ ID NO: 186 CCUCUACAGAACUUUACCUUG SEQ ID NO: 829 AGGUAAAGUUCUGUAGAGGCU SEQ ID NO: 1472 CCUCUACAGAACUUUACCU 0.178 AH0186 SEQ ID NO: 187 CUCUACAGAACUUUACCUUGU SEQ ID NO: 830 AAGGUAAAGUUCUGUAGAGGC SEQ ID NO: 1473 CUCUACAGAACUUUACCUU 0.183 AH0187 SEQ ID NO: 188 UCUACAGAACUUUACCUUGUG SEQ ID NO: 831 CAAGGUAAAGUUCUGUAGAGG SEQ ID NO: 1474 UCUACAGAACUUUACCUUG 0.244 AH0188 SEQ ID NO: 189 CUACAGAACUUUACCUUGUGU SEQ ID NO: 832 ACAAGGUAAAGUUCUGUAGAG SEQ ID NO: 1475 CUACAGAACUUUACCUUGU 0.079 AH0189 SEQ ID NO: 190 UACAGAACUUUACCUUGUGUU SEQ ID NO: 833 CACAAGGUAAAGUUCUGUAGA SEQ ID NO: 1476 UACAGAACUUUACCUUGUG 0.219 AH0190 SEQ ID NO: 191 ACAGAACUUUACCUUGUGUUU SEQ ID NO: 834 ACACAAGGUAAAGUUCUGUAG SEQ ID NO: 1477 ACAGAACUUUACCUUGUGU 0.387 AH0191 SEQ ID NO: 192 CAGAACUUUACCUUGUGUUUU SEQ ID NO: 835 AACACAAGGUAAAGUUCUGUA SEQ ID NO: 1478 CAGAACUUUACCUUGUGUU 0.171 AH0192 SEQ ID NO: 193 AGAACUUUACCUUGUGUUUUC SEQ ID NO: 836 AAACACAAGGUAAAGUUCUGU SEQ ID NO: 1479 AGAACUUUACCUUGUGUUU 0.133 AH0193 SEQ ID NO: 194 GAACUUUACCUUGUGUUUUCG SEQ ID NO: 837 AAAACACAAGGUAAAGUUCUG SEQ ID NO: 1480 GAACUUUACCUUGUGUUUU 0.081 AH0194 SEQ ID NO: 195 AACUUUACCUUGUGUUUUCGA SEQ ID NO: 838 GAAAACACAAGGUAAAGUUCU SEQ ID NO: 1481 AACUUUACCUUGUGUUUUC 0.347 AH0195 SEQ ID NO: 196 CUUUACCUUGUGUUUUCGAGC SEQ ID NO: 839 UCGAAAACACAAGGUAAAGUU SEQ ID NO: 1482 CUUUACCUUGUGUUUUCGA 0.453 AH0196 SEQ ID NO: 197 ACCUUGUGUUUUCGAGCCUAU SEQ ID NO: 840 AGGCUCGAAAACACAAGGUAA SEQ ID NO: 1483 ACCUUGUGUUUUCGAGCCU 0.164 AH0197 SEQ ID NO: 198 CCUUGUGUUUUCGAGCCUAUA SEQ ID NO: 841 UAGGCUCGAAAACACAAGGUA SEQ ID NO: 1484 CCUUGUGUUUUCGAGCCUA 0.081 AH0198 SEQ ID NO: 199 CUUGUGUUUUCGAGCCUAUAG SEQ ID NO: 842 AUAGGCUCGAAAACACAAGGU SEQ ID NO: 1485 CUUGUGUUUUCGAGCCUAU 0.110 AH0199 SEQ ID NO: 200 UUGUGUUUUCGAGCCUAUAGU SEQ ID NO: 843 UAUAGGCUCGAAAACACAAGG SEQ ID NO: 1486 UUGUGUUUUCGAGCCUAUA 0.137 AH0200 SEQ ID NO: 201 GUGUUUUCGAGCCUAUAGUGA SEQ ID NO: 844 ACUAUAGGCUCGAAAACACAA SEQ ID NO: 1487 GUGUUUUCGAGCCUAUAGU 0.125 AH0201 SEQ ID NO: 202 GUUUUCGAGCCUAUAGUGAUC SEQ ID NO: 845 UCACUAUAGGCUCGAAAACAC SEQ ID NO: 1488 GUUUUCGAGCCUAUAGUGA 0.074 AH0202 SEQ ID NO: 203 UUUUCGAGCCUAUAGUGAUCU SEQ ID NO: 846 AUCACUAUAGGCUCGAAAACA SEQ ID NO: 1489 UUUUCGAGCCUAUAGUGAU 0.136 AH0203 SEQ ID NO: 204 CGAGCCUAUAGUGAUCUCUCU SEQ ID NO: 847 AGAGAUCACUAUAGGCUCGAA SEQ ID NO: 1490 CGAGCCUAUAGUGAUCUCU 0.119 AH0204 SEQ ID NO: 205 GAGCCUAUAGUGAUCUCUCUC SEQ ID NO: 848 GAGAGAUCACUAUAGGCUCGA SEQ ID NO: 1491 GAGCCUAUAGUGAUCUCUC 0.127 AH0205 SEQ ID NO: 206 AGCCUAUAGUGAUCUCUCUCG SEQ ID NO: 849 AGAGAGAUCACUAUAGGCUCG SEQ ID NO: 1492 AGCCUAUAGUGAUCUCUCU 0.091 AH0206 SEQ ID NO: 207 GCCUAUAGUGAUCUCUCUCGU SEQ ID NO: 850 GAGAGAGAUCACUAUAGGCUC SEQ ID NO: 1493 GCCUAUAGUGAUCUCUCUC 0.090 AH0207 SEQ ID NO: 208 CCUAUAGUGAUCUCUCUCGUG SEQ ID NO: 851 CGAGAGAGAUCACUAUAGGCU SEQ ID NO: 1494 CCUAUAGUGAUCUCUCUCG 0.287 AH0208 SEQ ID NO: 209 CUAUAGUGAUCUCUCUCGUGC SEQ ID NO: 852 ACGAGAGAGAUCACUAUAGGC SEQ ID NO: 1495 CUAUAGUGAUCUCUCUCGU 0.088 AH0209 SEQ ID NO: 210 UAUAGUGAUCUCUCUCGUGCC SEQ ID NO: 853 CACGAGAGAGAUCACUAUAGG SEQ ID NO: 1496 UAUAGUGAUCUCUCUCGUG 0.355 AH0210 SEQ ID NO: 211 AGUGAUCUCUCUCGUGCCUAC SEQ ID NO: 854 AGGCACGAGAGAGAUCACUAU SEQ ID NO: 1497 AGUGAUCUCUCUCGUGCCU 0.089 AH0211 SEQ ID NO: 212 GUGAUCUCUCUCGUGCCUACA SEQ ID NO: 855 UAGGCACGAGAGAGAUCACUA SEQ ID NO: 1498 GUGAUCUCUCUCGUGCCUA 0.072 AH0212 SEQ ID NO: 213 UGAUCUCUCUCGUGCCUACAG SEQ ID NO: 856 GUAGGCACGAGAGAGAUCACU SEQ ID NO: 1499 UGAUCUCUCUCGUGCCUAC 0.158 AH0213 SEQ ID NO: 214 GAUCUCUCUCGUGCCUACAGC SEQ ID NO: 857 UGUAGGCACGAGAGAGAUCAC SEQ ID NO: 1500 GAUCUCUCUCGUGCCUACA 0.126 AH0214 SEQ ID NO: 215 CUCUCGUGCCUACAGCCUCUU SEQ ID NO: 858 GAGGCUGUAGGCACGAGAGAG SEQ ID NO: 1501 CUCUCGUGCCUACAGCCUC 0.196 AH0215 SEQ ID NO: 216 UCUCGUGCCUACAGCCUCUUC SEQ ID NO: 859 AGAGGCUGUAGGCACGAGAGA SEQ ID NO: 1502 UCUCGUGCCUACAGCCUCU 0.140 AH0216 SEQ ID NO: 217 CUCGUGCCUACAGCCUCUUCU SEQ ID NO: 860 AAGAGGCUGUAGGCACGAGAG SEQ ID NO: 1503 CUCGUGCCUACAGCCUCUU 0.198 AH0217 SEQ ID NO: 218 CGUGCCUACAGCCUCUUCUCC SEQ ID NO: 861 AGAAGAGGCUGUAGGCACGAG SEQ ID NO: 1504 CGUGCCUACAGCCUCUUCU 0.181 AH0218 SEQ ID NO: 219 GUGCCUACAGCCUCUUCUCCU SEQ ID NO: 862 GAGAAGAGGCUGUAGGCACGA SEQ ID NO: 1505 GUGCCUACAGCCUCUUCUC 0.101 AH0219 SEQ ID NO: 220 GCCUACAGCCUCUUCUCCUAC SEQ ID NO: 863 AGGAGAAGAGGCUGUAGGCAC SEQ ID NO: 1506 GCCUACAGCCUCUUCUCCU 0.100 AH0220 SEQ ID NO: 221 CCUACAGCCUCUUCUCCUACA SEQ ID NO: 864 UAGGAGAAGAGGCUGUAGGCA SEQ ID NO: 1507 CCUACAGCCUCUUCUCCUA 0.086 AH0221 SEQ ID NO: 222 CUACAGCCUCUUCUCCUACAA SEQ ID NO: 865 GUAGGAGAAGAGGCUGUAGGC SEQ ID NO: 1508 CUACAGCCUCUUCUCCUAC 0.153 AH0222 SEQ ID NO: 223 UACAGCCUCUUCUCCUACAAU SEQ ID NO: 866 UGUAGGAGAAGAGGCUGUAGG SEQ ID NO: 1509 UACAGCCUCUUCUCCUACA 0.221 AH0223 SEQ ID NO: 224 ACAGCCUCUUCUCCUACAAUA SEQ ID NO: 867 UUGUAGGAGAAGAGGCUGUAG SEQ ID NO: 1510 ACAGCCUCUUCUCCUACAA 0.137 AH0224 SEQ ID NO: 225 CAGCCUCUUCUCCUACAAUAC SEQ ID NO: 868 AUUGUAGGAGAAGAGGCUGUA SEQ ID NO: 1511 CAGCCUCUUCUCCUACAAU 0.184 AH0225 SEQ ID NO: 226 AGCCUCUUCUCCUACAAUACC SEQ ID NO: 869 UAUUGUAGGAGAAGAGGCUGU SEQ ID NO: 1512 AGCCUCUUCUCCUACAAUA 0.036 AH0226 SEQ ID NO: 227 GCCUCUUCUCCUACAAUACCC SEQ ID NO: 870 GUAUUGUAGGAGAAGAGGCUG SEQ ID NO: 1513 GCCUCUUCUCCUACAAUAC 0.172 AH0227 SEQ ID NO: 228 CCUCUUCUCCUACAAUACCCA SEQ ID NO: 871 GGUAUUGUAGGAGAAGAGGCU SEQ ID NO: 1514 CCUCUUCUCCUACAAUACC 0.116 AH0228 SEQ ID NO: 229 UCUUCUCCUACAAUACCCAAG SEQ ID NO: 872 UGGGUAUUGUAGGAGAAGAGG SEQ ID NO: 1515 UCUUCUCCUACAAUACCCA 0.450 AH0229 SEQ ID NO: 230 UCUCCUACAAUACCCAAGGCA SEQ ID NO: 873 CCUUGGGUAUUGUAGGAGAAG SEQ ID NO: 1516 UCUCCUACAAUACCCAAGG 0.486 AH0230 SEQ ID NO: 231 CUCCUACAAUACCCAAGGCAG SEQ ID NO: 874 GCCUUGGGUAUUGUAGGAGAA SEQ ID NO: 1517 CUCCUACAAUACCCAAGGC 0.303 AH0231 SEQ ID NO: 232 UCCUACAAUACCCAAGGCAGG SEQ ID NO: 875 UGCCUUGGGUAUUGUAGGAGA SEQ ID NO: 1518 UCCUACAAUACCCAAGGCA 0.206 AH0232 SEQ ID NO: 233 CCUACAAUACCCAAGGCAGGG SEQ ID NO: 876 CUGCCUUGGGUAUUGUAGGAG SEQ ID NO: 1519 CCUACAAUACCCAAGGCAG 0.324 AH0233 SEQ ID NO: 234 CUACAAUACCCAAGGCAGGGA SEQ ID NO: 877 CCUGCCUUGGGUAUUGUAGGA SEQ ID NO: 1520 CUACAAUACCCAAGGCAGG 0.223 AH0234 SEQ ID NO: 235 CAAUACCCAAGGCAGGGAUAA SEQ ID NO: 878 AUCCCUGCCUUGGGUAUUGUA SEQ ID NO: 1521 CAAUACCCAAGGCAGGGAU 0.323 AH0235 SEQ ID NO: 236 AUACCCAAGGCAGGGAUAAUG SEQ ID NO: 879 UUAUCCCUGCCUUGGGUAUUG SEQ ID NO: 1522 AUACCCAAGGCAGGGAUAA 0.207 AH0236 SEQ ID NO: 237 UACCCAAGGCAGGGAUAAUGA SEQ ID NO: 880 AUUAUCCCUGCCUUGGGUAUU SEQ ID NO: 1523 UACCCAAGGCAGGGAUAAU 0.450 AH0237 SEQ ID NO: 238 CCAAGGCAGGGAUAAUGAGCU SEQ ID NO: 881 CUCAUUAUCCCUGCCUUGGGU SEQ ID NO: 1524 CCAAGGCAGGGAUAAUGAG 0.424 AH0238 SEQ ID NO: 239 AAGGCAGGGAUAAUGAGCUAC SEQ ID NO: 882 AGCUCAUUAUCCCUGCCUUGG SEQ ID NO: 1525 AAGGCAGGGAUAAUGAGCU 0.172 AH0239 SEQ ID NO: 240 AGGCAGGGAUAAUGAGCUACU SEQ ID NO: 883 UAGCUCAUUAUCCCUGCCUUG SEQ ID NO: 1526 AGGCAGGGAUAAUGAGCUA 0.396 AH0240 SEQ ID NO: 241 GCAGGGAUAAUGAGCUACUAG SEQ ID NO: 884 AGUAGCUCAUUAUCCCUGCCU SEQ ID NO: 1527 GCAGGGAUAAUGAGCUACU 0.280 AH0241 SEQ ID NO: 242 CAGGGAUAAUGAGCUACUAGU SEQ ID NO: 885 UAGUAGCUCAUUAUCCCUGCC SEQ ID NO: 1528 CAGGGAUAAUGAGCUACUA 0.143 AH0242 SEQ ID NO: 243 AGGGAUAAUGAGCUACUAGUU SEQ ID NO: 886 CUAGUAGCUCAUUAUCCCUGC SEQ ID NO: 1529 AGGGAUAAUGAGCUACUAG 0.325 AH0243 SEQ ID NO: 244 GGGAUAAUGAGCUACUAGUUU SEQ ID NO: 887 ACUAGUAGCUCAUUAUCCCUG SEQ ID NO: 1530 GGGAUAAUGAGCUACUAGU 0.085 AH0244 SEQ ID NO: 245 GGAUAAUGAGCUACUAGUUUA SEQ ID NO: 888 AACUAGUAGCUCAUUAUCCCU SEQ ID NO: 1531 GGAUAAUGAGCUACUAGUU 0.073 AH0245 SEQ ID NO: 246 GAUAAUGAGCUACUAGUUUAU SEQ ID NO: 889 AAACUAGUAGCUCAUUAUCCC SEQ ID NO: 1532 GAUAAUGAGCUACUAGUUU 0.085 AH0246 SEQ ID NO: 247 AUAAUGAGCUACUAGUUUAUA SEQ ID NO: 890 UAAACUAGUAGCUCAUUAUCC SEQ ID NO: 1533 AUAAUGAGCUACUAGUUUA 0.115 AH0247 SEQ ID NO: 248 UAAUGAGCUACUAGUUUAUAA SEQ ID NO: 891 AUAAACUAGUAGCUCAUUAUC SEQ ID NO: 1534 UAAUGAGCUACUAGUUUAU 0.115 AH0248 SEQ ID NO: 249 AUGAGCUACUAGUUUAUAAAG SEQ ID NO: 892 UUAUAAACUAGUAGCUCAUUA SEQ ID NO: 1535 AUGAGCUACUAGUUUAUAA 0.195 AH0249 SEQ ID NO: 250 UGAGCUACUAGUUUAUAAAGA SEQ ID NO: 893 UUUAUAAACUAGUAGCUCAUU SEQ ID NO: 1536 UGAGCUACUAGUUUAUAAA 0.124 AH0250 SEQ ID NO: 251 GAGCUACUAGUUUAUAAAGAA SEQ ID NO: 894 CUUUAUAAACUAGUAGCUCAU SEQ ID NO: 1537 GAGCUACUAGUUUAUAAAG 0.449 AH0251 SEQ ID NO: 252 AGCUACUAGUUUAUAAAGAAA SEQ ID NO: 895 UCUUUAUAAACUAGUAGCUCA SEQ ID NO: 1538 AGCUACUAGUUUAUAAAGA 0.131 AH0252 SEQ ID NO: 253 GCUACUAGUUUAUAAAGAAAG SEQ ID NO: 896 UUCUUUAUAAACUAGUAGCUC SEQ ID NO: 1539 GCUACUAGUUUAUAAAGAA 0.092 AH0253 SEQ ID NO: 254 CUACUAGUUUAUAAAGAAAGA SEQ ID NO: 897 UUUCUUUAUAAACUAGUAGCU SEQ ID NO: 1540 CUACUAGUUUAUAAAGAAA 0.091 AH0254 SEQ ID NO: 255 AGUUUAUAAAGAAAGAGUUGG SEQ ID NO: 898 AACUCUUUCUUUAUAAACUAG SEQ ID NO: 1541 AGUUUAUAAAGAAAGAGUU 0.327 AH0255 SEQ ID NO: 256 AAGAAAGAGUUGGAGAGUAUA SEQ ID NO: 899 UACUCUCCAACUCUUUCUUUA SEQ ID NO: 1542 AAGAAAGAGUUGGAGAGUA 0.114 AH0256 SEQ ID NO: 257 AGAAAGAGUUGGAGAGUAUAG SEQ ID NO: 900 AUACUCUCCAACUCUUUCUUU SEQ ID NO: 1543 AGAAAGAGUUGGAGAGUAU 0.142 AH0257 SEQ ID NO: 258 GAAAGAGUUGGAGAGUAUAGU SEQ ID NO: 901 UAUACUCUCCAACUCUUUCUU SEQ ID NO: 1544 GAAAGAGUUGGAGAGUAUA 0.089 AH0258 SEQ ID NO: 259 AAGAGUUGGAGAGUAUAGUCU SEQ ID NO: 902 ACUAUACUCUCCAACUCUUUC SEQ ID NO: 1545 AAGAGUUGGAGAGUAUAGU 0.292 AH0259 SEQ ID NO: 260 AGAGUUGGAGAGUAUAGUCUA SEQ ID NO: 903 GACUAUACUCUCCAACUCUUU SEQ ID NO: 1546 AGAGUUGGAGAGUAUAGUC 0.178 AH0260 SEQ ID NO: 261 GAGUUGGAGAGUAUAGUCUAU SEQ ID NO: 904 AGACUAUACUCUCCAACUCUU SEQ ID NO: 1547 GAGUUGGAGAGUAUAGUCU 0.088 AH0261 SEQ ID NO: 262 AGUUGGAGAGUAUAGUCUAUA SEQ ID NO: 905 UAGACUAUACUCUCCAACUCU SEQ ID NO: 1548 AGUUGGAGAGUAUAGUCUA 0.034 AH0262 SEQ ID NO: 263 GUUGGAGAGUAUAGUCUAUAC SEQ ID NO: 906 AUAGACUAUACUCUCCAACUC SEQ ID NO: 1549 GUUGGAGAGUAUAGUCUAU 0.046 AH0263 SEQ ID NO: 264 UUGGAGAGUAUAGUCUAUACA SEQ ID NO: 907 UAUAGACUAUACUCUCCAACU SEQ ID NO: 1550 UUGGAGAGUAUAGUCUAUA 0.187 AH0264 SEQ ID NO: 265 UGGAGAGUAUAGUCUAUACAU SEQ ID NO: 908 GUAUAGACUAUACUCUCCAAC SEQ ID NO: 1551 UGGAGAGUAUAGUCUAUAC 0.357 AH0265 SEQ ID NO: 266 GGAGAGUAUAGUCUAUACAUU SEQ ID NO: 909 UGUAUAGACUAUACUCUCCAA SEQ ID NO: 1552 GGAGAGUAUAGUCUAUACA 0.133 AH0266 SEQ ID NO: 267 GAGAGUAUAGUCUAUACAUUG SEQ ID NO: 910 AUGUAUAGACUAUACUCUCCA SEQ ID NO: 1553 GAGAGUAUAGUCUAUACAU 0.430 AH0267 SEQ ID NO: 268 AGAGUAUAGUCUAUACAUUGG SEQ ID NO: 911 AAUGUAUAGACUAUACUCUCC SEQ ID NO: 1554 AGAGUAUAGUCUAUACAUU 0.079 AH0268 SEQ ID NO: 269 GAGUAUAGUCUAUACAUUGGA SEQ ID NO: 912 CAAUGUAUAGACUAUACUCUC SEQ ID NO: 1555 GAGUAUAGUCUAUACAUUG 0.139 AH0269 SEQ ID NO: 270 AGUAUAGUCUAUACAUUGGAA SEQ ID NO: 913 CCAAUGUAUAGACUAUACUCU SEQ ID NO: 1556 AGUAUAGUCUAUACAUUGG 0.291 AH0270 SEQ ID NO: 271 GUAUAGUCUAUACAUUGGAAG SEQ ID NO: 914 UCCAAUGUAUAGACUAUACUC SEQ ID NO: 1557 GUAUAGUCUAUACAUUGGA 0.145 AH0271 SEQ ID NO: 272 GUCUAUACAUUGGAAGACACA SEQ ID NO: 915 UGUCUUCCAAUGUAUAGACUA SEQ ID NO: 1558 GUCUAUACAUUGGAAGACA 0.249 AH0272 SEQ ID NO: 273 CUAUACAUUGGAAGACACAAA SEQ ID NO: 916 UGUGUCUUCCAAUGUAUAGAC SEQ ID NO: 1559 CUAUACAUUGGAAGACACA 0.165 AH0273 SEQ ID NO: 274 UAUACAUUGGAAGACACAAAG SEQ ID NO: 917 UUGUGUCUUCCAAUGUAUAGA SEQ ID NO: 1560 UAUACAUUGGAAGACACAA 0.312 AH0274 SEQ ID NO: 275 AUACAUUGGAAGACACAAAGU SEQ ID NO: 918 UUUGUGUCUUCCAAUGUAUAG SEQ ID NO: 1561 AUACAUUGGAAGACACAAA 0.296 AH0275 SEQ ID NO: 276 ACAUUGGAAGACACAAAGUUA SEQ ID NO: 919 ACUUUGUGUCUUCCAAUGUAU SEQ ID NO: 1562 ACAUUGGAAGACACAAAGU 0.362 AH0276 SEQ ID NO: 277 CAUUGGAAGACACAAAGUUAC SEQ ID NO: 920 AACUUUGUGUCUUCCAAUGUA SEQ ID NO: 1563 CAUUGGAAGACACAAAGUU 0.098 AH0277 SEQ ID NO: 278 AUUGGAAGACACAAAGUUACA SEQ ID NO: 921 UAACUUUGUGUCUUCCAAUGU SEQ ID NO: 1564 AUUGGAAGACACAAAGUUA 0.165 AH0278 SEQ ID NO: 279 UGGAAGACACAAAGUUACAUC SEQ ID NO: 922 UGUAACUUUGUGUCUUCCAAU SEQ ID NO: 1565 UGGAAGACACAAAGUUACA 0.257 AH0279 SEQ ID NO: 280 GGAAGACACAAAGUUACAUCC SEQ ID NO: 923 AUGUAACUUUGUGUCUUCCAA SEQ ID NO: 1566 GGAAGACACAAAGUUACAU 0.191 AH0280 SEQ ID NO: 281 GAAGACACAAAGUUACAUCCA SEQ ID NO: 924 GAUGUAACUUUGUGUCUUCCA SEQ ID NO: 1567 GAAGACACAAAGUUACAUC 0.353 AH0281 SEQ ID NO: 282 AAGACACAAAGUUACAUCCAA SEQ ID NO: 925 GGAUGUAACUUUGUGUCUUCC SEQ ID NO: 1568 AAGACACAAAGUUACAUCC 0.390 AH0282 SEQ ID NO: 283 AGACACAAAGUUACAUCCAAA SEQ ID NO: 926 UGGAUGUAACUUUGUGUCUUC SEQ ID NO: 1569 AGACACAAAGUUACAUCCA 0.281 AH0283 SEQ ID NO: 284 GACACAAAGUUACAUCCAAAG SEQ ID NO: 927 UUGGAUGUAACUUUGUGUCUU SEQ ID NO: 1570 GACACAAAGUUACAUCCAA 0.059 AH0284 SEQ ID NO: 285 ACACAAAGUUACAUCCAAAGU SEQ ID NO: 928 UUUGGAUGUAACUUUGUGUCU SEQ ID NO: 1571 ACACAAAGUUACAUCCAAA 0.047 AH0285 SEQ ID NO: 286 CACAAAGUUACAUCCAAAGUU SEQ ID NO: 929 CUUUGGAUGUAACUUUGUGUC SEQ ID NO: 1572 CACAAAGUUACAUCCAAAG 0.246 AH0286 SEQ ID NO: 287 CAAAGUUACAUCCAAAGUUAU SEQ ID NO: 930 AACUUUGGAUGUAACUUUGUG SEQ ID NO: 1573 CAAAGUUACAUCCAAAGUU 0.225 AH0287 SEQ ID NO: 288 AAAGUUACAUCCAAAGUUAUC SEQ ID NO: 931 UAACUUUGGAUGUAACUUUGU SEQ ID NO: 1574 AAAGUUACAUCCAAAGUUA 0.071 AH0288 SEQ ID NO: 289 AAGUUACAUCCAAAGUUAUCG SEQ ID NO: 932 AUAACUUUGGAUGUAACUUUG SEQ ID NO: 1575 AAGUUACAUCCAAAGUUAU 0.088 AH0289 SEQ ID NO: 290 AGUUACAUCCAAAGUUAUCGA SEQ ID NO: 933 GAUAACUUUGGAUGUAACUUU SEQ ID NO: 1576 AGUUACAUCCAAAGUUAUC 0.276 AH0290 SEQ ID NO: 291 GUUACAUCCAAAGUUAUCGAA SEQ ID NO: 934 CGAUAACUUUGGAUGUAACUU SEQ ID NO: 1577 GUUACAUCCAAAGUUAUCG 0.240 AH0291 SEQ ID NO: 292 UUACAUCCAAAGUUAUCGAAA SEQ ID NO: 935 UCGAUAACUUUGGAUGUAACU SEQ ID NO: 1578 UUACAUCCAAAGUUAUCGA 0.352 AH0292 SEQ ID NO: 293 UACAUCCAAAGUUAUCGAAAA SEQ ID NO: 936 UUCGAUAACUUUGGAUGUAAC SEQ ID NO: 1579 UACAUCCAAAGUUAUCGAA 0.250 AH0293 SEQ ID NO: 294 ACAUCCAAAGUUAUCGAAAAG SEQ ID NO: 937 UUUCGAUAACUUUGGAUGUAA SEQ ID NO: 1580 ACAUCCAAAGUUAUCGAAA 0.266 AH0294 SEQ ID NO: 295 CAUCCAAAGUUAUCGAAAAGU SEQ ID NO: 938 UUUUCGAUAACUUUGGAUGUA SEQ ID NO: 1581 CAUCCAAAGUUAUCGAAAA 0.052 AH0295 SEQ ID NO: 296 AUCCAAAGUUAUCGAAAAGUU SEQ ID NO: 939 CUUUUCGAUAACUUUGGAUGU SEQ ID NO: 1582 AUCCAAAGUUAUCGAAAAG 0.245 AH0296 SEQ ID NO: 297 UCCAAAGUUAUCGAAAAGUUC SEQ ID NO: 940 ACUUUUCGAUAACUUUGGAUG SEQ ID NO: 1583 UCCAAAGUUAUCGAAAAGU 0.378 AH0297 SEQ ID NO: 298 CCAAAGUUAUCGAAAAGUUCC SEQ ID NO: 941 AACUUUUCGAUAACUUUGGAU SEQ ID NO: 1584 CCAAAGUUAUCGAAAAGUU 0.131 AH0298 SEQ ID NO: 299 CAAAGUUAUCGAAAAGUUCCC SEQ ID NO: 942 GAACUUUUCGAUAACUUUGGA SEQ ID NO: 1585 CAAAGUUAUCGAAAAGUUC 0.062 AH0299 SEQ ID NO: 300 CGAAAAGUUCCCGGCUCCAGU SEQ ID NO: 943 UGGAGCCGGGAACUUUUCGAU SEQ ID NO: 1586 CGAAAAGUUCCCGGCUCCA 0.329 AH0300 SEQ ID NO: 301 AAAAGUUCCCGGCUCCAGUGC SEQ ID NO: 944 ACUGGAGCCGGGAACUUUUCG SEQ ID NO: 1587 AAAAGUUCCCGGCUCCAGU 0.346 AH0301 SEQ ID NO: 302 CCCGGCUCCAGUGCACAUCUG SEQ ID NO: 945 GAUGUGCACUGGAGCCGGGAA SEQ ID NO: 1588 CCCGGCUCCAGUGCACAUC 0.368 AH0302 SEQ ID NO: 303 CGGCUCCAGUGCACAUCUGUG SEQ ID NO: 946 CAGAUGUGCACUGGAGCCGGG SEQ ID NO: 1589 CGGCUCCAGUGCACAUCUG 0.296 AH0303 SEQ ID NO: 304 GGCUCCAGUGCACAUCUGUGU SEQ ID NO: 947 ACAGAUGUGCACUGGAGCCGG SEQ ID NO: 1590 GGCUCCAGUGCACAUCUGU 0.273 AH0304 SEQ ID NO: 305 GCUCCAGUGCACAUCUGUGUG SEQ ID NO: 948 CACAGAUGUGCACUGGAGCCG SEQ ID NO: 1591 GCUCCAGUGCACAUCUGUG 0.075 AH0305 SEQ ID NO: 306 CUCCAGUGCACAUCUGUGUGA SEQ ID NO: 949 ACACAGAUGUGCACUGGAGCC SEQ ID NO: 1592 CUCCAGUGCACAUCUGUGU 0.280 AH0306 SEQ ID NO: 307 CCAGUGCACAUCUGUGUGAGC SEQ ID NO: 950 UCACACAGAUGUGCACUGGAG SEQ ID NO: 1593 CCAGUGCACAUCUGUGUGA 0.479 AH0307 SEQ ID NO: 308 GUGCACAUCUGUGUGAGCUGG SEQ ID NO: 951 AGCUCACACAGAUGUGCACUG SEQ ID NO: 1594 GUGCACAUCUGUGUGAGCU 0.452 AH0308 SEQ ID NO: 309 GCACAUCUGUGUGAGCUGGGA SEQ ID NO: 952 CCAGCUCACACAGAUGUGCAC SEQ ID NO: 1595 GCACAUCUGUGUGAGCUGG 0.377 AH0309 SEQ ID NO: 310 ACAUCUGUGUGAGCUGGGAGU SEQ ID NO: 953 UCCCAGCUCACACAGAUGUGC SEQ ID NO: 1596 ACAUCUGUGUGAGCUGGGA 0.255 AH0310 SEQ ID NO: 311 AUCUGUGUGAGCUGGGAGUCC SEQ ID NO: 954 ACUCCCAGCUCACACAGAUGU SEQ ID NO: 1597 AUCUGUGUGAGCUGGGAGU 0.317 AH0311 SEQ ID NO: 312 UGUGUGAGCUGGGAGUCCUCA SEQ ID NO: 955 AGGACUCCCAGCUCACACAGA SEQ ID NO: 1598 UGUGUGAGCUGGGAGUCCU 0.234 AH0312 SEQ ID NO: 313 GUGUGAGCUGGGAGUCCUCAU SEQ ID NO: 956 GAGGACUCCCAGCUCACACAG SEQ ID NO: 1599 GUGUGAGCUGGGAGUCCUC 0.139 AH0313 SEQ ID NO: 314 AGCUGGGAGUCCUCAUCAGGU SEQ ID NO: 957 CUGAUGAGGACUCCCAGCUCA SEQ ID NO: 1600 AGCUGGGAGUCCUCAUCAG 0.237 AH0314 SEQ ID NO: 315 GCUGGGAGUCCUCAUCAGGUA SEQ ID NO: 958 CCUGAUGAGGACUCCCAGCUC SEQ ID NO: 1601 GCUGGGAGUCCUCAUCAGG 0.223 AH0315 SEQ ID NO: 316 CUGGGAGUCCUCAUCAGGUAU SEQ ID NO: 959 ACCUGAUGAGGACUCCCAGCU SEQ ID NO: 1602 CUGGGAGUCCUCAUCAGGU 0.093 AH0316 SEQ ID NO: 317 UGGGAGUCCUCAUCAGGUAUU SEQ ID NO: 960 UACCUGAUGAGGACUCCCAGC SEQ ID NO: 1603 UGGGAGUCCUCAUCAGGUA 0.062 AH0317 SEQ ID NO: 318 GGGAGUCCUCAUCAGGUAUUG SEQ ID NO: 961 AUACCUGAUGAGGACUCCCAG SEQ ID NO: 1604 GGGAGUCCUCAUCAGGUAU 0.218 AH0318 SEQ ID NO: 319 GGAGUCCUCAUCAGGUAUUGC SEQ ID NO: 962 AAUACCUGAUGAGGACUCCCA SEQ ID NO: 1605 GGAGUCCUCAUCAGGUAUU 0.117 AH0319 SEQ ID NO: 320 GAGUCCUCAUCAGGUAUUGCU SEQ ID NO: 963 CAAUACCUGAUGAGGACUCCC SEQ ID NO: 1606 GAGUCCUCAUCAGGUAUUG 0.271 AH0320 SEQ ID NO: 321 GUCCUCAUCAGGUAUUGCUGA SEQ ID NO: 964 AGCAAUACCUGAUGAGGACUC SEQ ID NO: 1607 GUCCUCAUCAGGUAUUGCU 0.076 AH0321 SEQ ID NO: 322 UCCUCAUCAGGUAUUGCUGAA SEQ ID NO: 965 CAGCAAUACCUGAUGAGGACU SEQ ID NO: 1608 UCCUCAUCAGGUAUUGCUG 0.343 AH0322 SEQ ID NO: 323 CCUCAUCAGGUAUUGCUGAAU SEQ ID NO: 966 UCAGCAAUACCUGAUGAGGAC SEQ ID NO: 1609 CCUCAUCAGGUAUUGCUGA 0.104 AH0323 SEQ ID NO: 324 CUCAUCAGGUAUUGCUGAAUU SEQ ID NO: 967 UUCAGCAAUACCUGAUGAGGA SEQ ID NO: 1610 CUCAUCAGGUAUUGCUGAA 0.105 AH0324 SEQ ID NO: 325 UCAUCAGGUAUUGCUGAAUUU SEQ ID NO: 968 AUUCAGCAAUACCUGAUGAGG SEQ ID NO: 1611 UCAUCAGGUAUUGCUGAAU 0.246 AH0325 SEQ ID NO: 326 CAUCAGGUAUUGCUGAAUUUU SEQ ID NO: 969 AAUUCAGCAAUACCUGAUGAG SEQ ID NO: 1612 CAUCAGGUAUUGCUGAAUU 0.137 AH0326 SEQ ID NO: 327 AUCAGGUAUUGCUGAAUUUUG SEQ ID NO: 970 AAAUUCAGCAAUACCUGAUGA SEQ ID NO: 1613 AUCAGGUAUUGCUGAAUUU 0.067 AH0327 SEQ ID NO: 328 UCAGGUAUUGCUGAAUUUUGG SEQ ID NO: 971 AAAAUUCAGCAAUACCUGAUG SEQ ID NO: 1614 UCAGGUAUUGCUGAAUUUU 0.243 AH0328 SEQ ID NO: 329 CAGGUAUUGCUGAAUUUUGGA SEQ ID NO: 972 CAAAAUUCAGCAAUACCUGAU SEQ ID NO: 1615 CAGGUAUUGCUGAAUUUUG 0.240 AH0329 SEQ ID NO: 330 AGGUAUUGCUGAAUUUUGGAU SEQ ID NO: 973 CCAAAAUUCAGCAAUACCUGA SEQ ID NO: 1616 AGGUAUUGCUGAAUUUUGG 0.069 AH0330 SEQ ID NO: 331 GGUAUUGCUGAAUUUUGGAUC SEQ ID NO: 974 UCCAAAAUUCAGCAAUACCUG SEQ ID NO: 1617 GGUAUUGCUGAAUUUUGGA 0.078 AH0331 SEQ ID NO: 332 GUAUUGCUGAAUUUUGGAUCA SEQ ID NO: 975 AUCCAAAAUUCAGCAAUACCU SEQ ID NO: 1618 GUAUUGCUGAAUUUUGGAU 0.165 AH0332 SEQ ID NO: 333 AUUGCUGAAUUUUGGAUCAAU SEQ ID NO: 976 UGAUCCAAAAUUCAGCAAUAC SEQ ID NO: 1619 AUUGCUGAAUUUUGGAUCA 0.178 AH0333 SEQ ID NO: 334 UGCUGAAUUUUGGAUCAAUGG SEQ ID NO: 977 AUUGAUCCAAAAUUCAGCAAU SEQ ID NO: 1620 UGCUGAAUUUUGGAUCAAU 0.220 AH0334 SEQ ID NO: 335 GCUGAAUUUUGGAUCAAUGGG SEQ ID NO: 978 CAUUGAUCCAAAAUUCAGCAA SEQ ID NO: 1621 GCUGAAUUUUGGAUCAAUG 0.160 AH0335 SEQ ID NO: 336 CUGAAUUUUGGAUCAAUGGGA SEQ ID NO: 979 CCAUUGAUCCAAAAUUCAGCA SEQ ID NO: 1622 CUGAAUUUUGGAUCAAUGG 0.311 AH0336 SEQ ID NO: 337 GAAUUUUGGAUCAAUGGGACA SEQ ID NO: 980 UCCCAUUGAUCCAAAAUUCAG SEQ ID NO: 1623 GAAUUUUGGAUCAAUGGGA 0.130 AH0337 SEQ ID NO: 338 GGAUCAAUGGGACACCUUUGG SEQ ID NO: 981 AAAGGUGUCCCAUUGAUCCAA SEQ ID NO: 1624 GGAUCAAUGGGACACCUUU 0.129 AH0338 SEQ ID NO: 339 CAAUGGGACACCUUUGGUGAA SEQ ID NO: 982 CACCAAAGGUGUCCCAUUGAU SEQ ID NO: 1625 CAAUGGGACACCUUUGGUG 0.365 AH0339 SEQ ID NO: 340 AAUGGGACACCUUUGGUGAAA SEQ ID NO: 983 UCACCAAAGGUGUCCCAUUGA SEQ ID NO: 1626 AAUGGGACACCUUUGGUGA 0.257 AH0340 SEQ ID NO: 341 AUGGGACACCUUUGGUGAAAA SEQ ID NO: 984 UUCACCAAAGGUGUCCCAUUG SEQ ID NO: 1627 AUGGGACACCUUUGGUGAA 0.333 AH0341 SEQ ID NO: 342 UGGGACACCUUUGGUGAAAAA SEQ ID NO: 985 UUUCACCAAAGGUGUCCCAUU SEQ ID NO: 1628 UGGGACACCUUUGGUGAAA 0.326 AH0342 SEQ ID NO: 343 GGGACACCUUUGGUGAAAAAG SEQ ID NO: 986 UUUUCACCAAAGGUGUCCCAU SEQ ID NO: 1629 GGGACACCUUUGGUGAAAA 0.195 AH0343 SEQ ID NO: 344 GGACACCUUUGGUGAAAAAGG SEQ ID NO: 987 UUUUUCACCAAAGGUGUCCCA SEQ ID NO: 1630 GGACACCUUUGGUGAAAAA 0.122 AH0344 SEQ ID NO: 345 ACCUUUGGUGAAAAAGGGUCU SEQ ID NO: 988 ACCCUUUUUCACCAAAGGUGU SEQ ID NO: 1631 ACCUUUGGUGAAAAAGGGU 0.253 AH0345 SEQ ID NO: 346 CCUUUGGUGAAAAAGGGUCUG SEQ ID NO: 989 GACCCUUUUUCACCAAAGGUG SEQ ID NO: 1632 CCUUUGGUGAAAAAGGGUC 0.440 AH0346 SEQ ID NO: 347 CUUUGGUGAAAAAGGGUCUGC SEQ ID NO: 990 AGACCCUUUUUCACCAAAGGU SEQ ID NO: 1633 CUUUGGUGAAAAAGGGUCU 0.125 AH0347 SEQ ID NO: 348 GGUGAAAAAGGGUCUGCGACA SEQ ID NO: 991 UCGCAGACCCUUUUUCACCAA SEQ ID NO: 1634 GGUGAAAAAGGGUCUGCGA 0.082 AH0348 SEQ ID NO: 349 GUGAAAAAGGGUCUGCGACAG SEQ ID NO: 992 GUCGCAGACCCUUUUUCACCA SEQ ID NO: 1635 GUGAAAAAGGGUCUGCGAC 0.270 AH0349 SEQ ID NO: 350 UGAAAAAGGGUCUGCGACAGG SEQ ID NO: 993 UGUCGCAGACCCUUUUUCACC SEQ ID NO: 1636 UGAAAAAGGGUCUGCGACA 0.375 AH0350 SEQ ID NO: 351 GAAAAAGGGUCUGCGACAGGG SEQ ID NO: 994 CUGUCGCAGACCCUUUUUCAC SEQ ID NO: 1637 GAAAAAGGGUCUGCGACAG 0.376 AH0351 SEQ ID NO: 352 AAAGGGUCUGCGACAGGGUUA SEQ ID NO: 995 ACCCUGUCGCAGACCCUUUUU SEQ ID NO: 1638 AAAGGGUCUGCGACAGGGU 0.326 AH0352 SEQ ID NO: 353 AAGGGUCUGCGACAGGGUUAC SEQ ID NO: 996 AACCCUGUCGCAGACCCUUUU SEQ ID NO: 1639 AAGGGUCUGCGACAGGGUU 0.192 AH0353 SEQ ID NO: 354 AGGGUCUGCGACAGGGUUACU SEQ ID NO: 997 UAACCCUGUCGCAGACCCUUU SEQ ID NO: 1640 AGGGUCUGCGACAGGGUUA 0.106 AH0354 SEQ ID NO: 355 GGGUCUGCGACAGGGUUACUU SEQ ID NO: 998 GUAACCCUGUCGCAGACCCUU SEQ ID NO: 1641 GGGUCUGCGACAGGGUUAC 0.098 AH0355 SEQ ID NO: 356 GGUCUGCGACAGGGUUACUUU SEQ ID NO: 999 AGUAACCCUGUCGCAGACCCU SEQ ID NO: 1642 GGUCUGCGACAGGGUUACU 0.195 AH0356 SEQ ID NO: 357 GUCUGCGACAGGGUUACUUUG SEQ ID NO: 1000 AAGUAACCCUGUCGCAGACCC SEQ ID NO: 1643 GUCUGCGACAGGGUUACUU 0.154 AH0357 SEQ ID NO: 358 UCUGCGACAGGGUUACUUUGU SEQ ID NO: 1001 AAAGUAACCCUGUCGCAGACC SEQ ID NO: 1644 UCUGCGACAGGGUUACUUU 0.126 AH0358 SEQ ID NO: 359 CUGCGACAGGGUUACUUUGUA SEQ ID NO: 1002 CAAAGUAACCCUGUCGCAGAC SEQ ID NO: 1645 CUGCGACAGGGUUACUUUG 0.120 AH0359 SEQ ID NO: 360 UGCGACAGGGUUACUUUGUAG SEQ ID NO: 1003 ACAAAGUAACCCUGUCGCAGA SEQ ID NO: 1646 UGCGACAGGGUUACUUUGU 0.438 AH0360 SEQ ID NO: 361 GCGACAGGGUUACUUUGUAGA SEQ ID NO: 1004 UACAAAGUAACCCUGUCGCAG SEQ ID NO: 1647 GCGACAGGGUUACUUUGUA 0.104 AH0361 SEQ ID NO: 362 CGACAGGGUUACUUUGUAGAA SEQ ID NO: 1005 CUACAAAGUAACCCUGUCGCA SEQ ID NO: 1648 CGACAGGGUUACUUUGUAG 0.290 AH0362 SEQ ID NO: 363 GACAGGGUUACUUUGUAGAAG SEQ ID NO: 1006 UCUACAAAGUAACCCUGUCGC SEQ ID NO: 1649 GACAGGGUUACUUUGUAGA 0.453 AH0363 SEQ ID NO: 364 ACAGGGUUACUUUGUAGAAGC SEQ ID NO: 1007 UUCUACAAAGUAACCCUGUCG SEQ ID NO: 1650 ACAGGGUUACUUUGUAGAA 0.467 AH0364 SEQ ID NO: 365 CAGGGUUACUUUGUAGAAGCU SEQ ID NO: 1008 CUUCUACAAAGUAACCCUGUC SEQ ID NO: 1651 CAGGGUUACUUUGUAGAAG 0.156 AH0365 SEQ ID NO: 366 AGGGUUACUUUGUAGAAGCUC SEQ ID NO: 1009 GCUUCUACAAAGUAACCCUGU SEQ ID NO: 1652 AGGGUUACUUUGUAGAAGC 0.280 AH0366 SEQ ID NO: 367 GGGUUACUUUGUAGAAGCUCA SEQ ID NO: 1010 AGCUUCUACAAAGUAACCCUG SEQ ID NO: 1653 GGGUUACUUUGUAGAAGCU 0.179 AH0367 SEQ ID NO: 368 GGUUACUUUGUAGAAGCUCAG SEQ ID NO: 1011 GAGCUUCUACAAAGUAACCCU SEQ ID NO: 1654 GGUUACUUUGUAGAAGCUC 0.222 AH0368 SEQ ID NO: 369 GUUACUUUGUAGAAGCUCAGC SEQ ID NO: 1012 UGAGCUUCUACAAAGUAACCC SEQ ID NO: 1655 GUUACUUUGUAGAAGCUCA 0.083 AH0369 SEQ ID NO: 370 AGAAGCUCAGCCCAAGAUUGU SEQ ID NO: 1013 AAUCUUGGGCUGAGCUUCUAC SEQ ID NO: 1656 AGAAGCUCAGCCCAAGAUU 0.313 AH0370 SEQ ID NO: 371 GAAGCUCAGCCCAAGAUUGUC SEQ ID NO: 1014 CAAUCUUGGGCUGAGCUUCUA SEQ ID NO: 1657 GAAGCUCAGCCCAAGAUUG 0.088 AH0371 SEQ ID NO: 372 AAGCUCAGCCCAAGAUUGUCC SEQ ID NO: 1015 ACAAUCUUGGGCUGAGCUUCU SEQ ID NO: 1658 AAGCUCAGCCCAAGAUUGU 0.093 AH0372 SEQ ID NO: 373 AGCUCAGCCCAAGAUUGUCCU SEQ ID NO: 1016 GACAAUCUUGGGCUGAGCUUC SEQ ID NO: 1659 AGCUCAGCCCAAGAUUGUC 0.142 AH0373 SEQ ID NO: 374 CUCAGCCCAAGAUUGUCCUGG SEQ ID NO: 1017 AGGACAAUCUUGGGCUGAGCU SEQ ID NO: 1660 CUCAGCCCAAGAUUGUCCU 0.255 AH0374 SEQ ID NO: 375 AGCCCAAGAUUGUCCUGGGGC SEQ ID NO: 1018 CCCAGGACAAUCUUGGGCUGA SEQ ID NO: 1661 AGCCCAAGAUUGUCCUGGG 0.308 AH0375 SEQ ID NO: 376 CCAAGAUUGUCCUGGGGCAGG SEQ ID NO: 1019 UGCCCCAGGACAAUCUUGGGC SEQ ID NO: 1662 CCAAGAUUGUCCUGGGGCA 0.097 AH0376 SEQ ID NO: 377 CAAGAUUGUCCUGGGGCAGGA SEQ ID NO: 1020 CUGCCCCAGGACAAUCUUGGG SEQ ID NO: 1663 CAAGAUUGUCCUGGGGCAG 0.316 AH0377 SEQ ID NO: 378 AGAUUGUCCUGGGGCAGGAAC SEQ ID NO: 1021 UCCUGCCCCAGGACAAUCUUG SEQ ID NO: 1664 AGAUUGUCCUGGGGCAGGA 0.116 AH0378 SEQ ID NO: 379 GAUUGUCCUGGGGCAGGAACA SEQ ID NO: 1022 UUCCUGCCCCAGGACAAUCUU SEQ ID NO: 1665 GAUUGUCCUGGGGCAGGAA 0.193 AH0379 SEQ ID NO: 380 UUGUCCUGGGGCAGGAACAGG SEQ ID NO: 1023 UGUUCCUGCCCCAGGACAAUC SEQ ID NO: 1666 UUGUCCUGGGGCAGGAACA 0.432 AH0380 SEQ ID NO: 381 UCCUGGGGCAGGAACAGGAUU SEQ ID NO: 1024 UCCUGUUCCUGCCCCAGGACA SEQ ID NO: 1667 UCCUGGGGCAGGAACAGGA 0.170 AH0381 SEQ ID NO: 382 CUGGGGCAGGAACAGGAUUCC SEQ ID NO: 1025 AAUCCUGUUCCUGCCCCAGGA SEQ ID NO: 1668 CUGGGGCAGGAACAGGAUU 0.448 AH0382 SEQ ID NO: 383 UGGGGCAGGAACAGGAUUCCU SEQ ID NO: 1026 GAAUCCUGUUCCUGCCCCAGG SEQ ID NO: 1669 UGGGGCAGGAACAGGAUUC 0.494 AH0383 SEQ ID NO: 384 GGGGCAGGAACAGGAUUCCUA SEQ ID NO: 1027 GGAAUCCUGUUCCUGCCCCAG SEQ ID NO: 1670 GGGGCAGGAACAGGAUUCC 0.244 AH0384 SEQ ID NO: 385 GGCAGGAACAGGAUUCCUAUG SEQ ID NO: 1028 UAGGAAUCCUGUUCCUGCCCC SEQ ID NO: 1671 GGCAGGAACAGGAUUCCUA 0.074 AH0385 SEQ ID NO: 386 GCAGGAACAGGAUUCCUAUGG SEQ ID NO: 1029 AUAGGAAUCCUGUUCCUGCCC SEQ ID NO: 1672 GCAGGAACAGGAUUCCUAU 0.146 AH0386 SEQ ID NO: 387 CAGGAACAGGAUUCCUAUGGG SEQ ID NO: 1030 CAUAGGAAUCCUGUUCCUGCC SEQ ID NO: 1673 CAGGAACAGGAUUCCUAUG 0.280 AH0387 SEQ ID NO: 388 GGAACAGGAUUCCUAUGGGGG SEQ ID NO: 1031 CCCAUAGGAAUCCUGUUCCUG SEQ ID NO: 1674 GGAACAGGAUUCCUAUGGG 0.260 AH0388 SEQ ID NO: 389 GAACAGGAUUCCUAUGGGGGC SEQ ID NO: 1032 CCCCAUAGGAAUCCUGUUCCU SEQ ID NO: 1675 GAACAGGAUUCCUAUGGGG 0.437 AH0389 SEQ ID NO: 390 ACAGGAUUCCUAUGGGGGCAA SEQ ID NO: 1033 GCCCCCAUAGGAAUCCUGUUC SEQ ID NO: 1676 ACAGGAUUCCUAUGGGGGC 0.349 AH0390 SEQ ID NO: 391 CAGGAUUCCUAUGGGGGCAAG SEQ ID NO: 1034 UGCCCCCAUAGGAAUCCUGUU SEQ ID NO: 1677 CAGGAUUCCUAUGGGGGCA 0.279 AH0391 SEQ ID NO: 392 GGAUUCCUAUGGGGGCAAGUU SEQ ID NO: 1035 CUUGCCCCCAUAGGAAUCCUG SEQ ID NO: 1678 GGAUUCCUAUGGGGGCAAG 0.153 AH0392 SEQ ID NO: 393 GAUUCCUAUGGGGGCAAGUUU SEQ ID NO: 1036 ACUUGCCCCCAUAGGAAUCCU SEQ ID NO: 1679 GAUUCCUAUGGGGGCAAGU 0.257 AH0393 SEQ ID NO: 394 AUUCCUAUGGGGGCAAGUUUG SEQ ID NO: 1037 AACUUGCCCCCAUAGGAAUCC SEQ ID NO: 1680 AUUCCUAUGGGGGCAAGUU 0.373 AH0394 SEQ ID NO: 395 UUCCUAUGGGGGCAAGUUUGA SEQ ID NO: 1038 AAACUUGCCCCCAUAGGAAUC SEQ ID NO: 1681 UUCCUAUGGGGGCAAGUUU 0.481 AH0395 SEQ ID NO: 396 UCCUAUGGGGGCAAGUUUGAU SEQ ID NO: 1039 CAAACUUGCCCCCAUAGGAAU SEQ ID NO: 1682 UCCUAUGGGGGCAAGUUUG 0.395 AH0396 SEQ ID NO: 397 CCUAUGGGGGCAAGUUUGAUA SEQ ID NO: 1040 UCAAACUUGCCCCCAUAGGAA SEQ ID NO: 1683 CCUAUGGGGGCAAGUUUGA 0.272 AH0397 SEQ ID NO: 398 CUAUGGGGGCAAGUUUGAUAG SEQ ID NO: 1041 AUCAAACUUGCCCCCAUAGGA SEQ ID NO: 1684 CUAUGGGGGCAAGUUUGAU 0.198 AH0398 SEQ ID NO: 399 UAUGGGGGCAAGUUUGAUAGG SEQ ID NO: 1042 UAUCAAACUUGCCCCCAUAGG SEQ ID NO: 1685 UAUGGGGGCAAGUUUGAUA 0.481 AH0399 SEQ ID NO: 400 GGGGGCAAGUUUGAUAGGAGC SEQ ID NO: 1043 UCCUAUCAAACUUGCCCCCAU SEQ ID NO: 1686 GGGGGCAAGUUUGAUAGGA 0.268 AH0400 SEQ ID NO: 401 GGGGCAAGUUUGAUAGGAGCC SEQ ID NO: 1044 CUCCUAUCAAACUUGCCCCCA SEQ ID NO: 1687 GGGGCAAGUUUGAUAGGAG 0.100 AH0401 SEQ ID NO: 402 GGGCAAGUUUGAUAGGAGCCA SEQ ID NO: 1045 GCUCCUAUCAAACUUGCCCCC SEQ ID NO: 1688 GGGCAAGUUUGAUAGGAGC 0.114 AH0402 SEQ ID NO: 403 GGCAAGUUUGAUAGGAGCCAG SEQ ID NO: 1046 GGCUCCUAUCAAACUUGCCCC SEQ ID NO: 1689 GGCAAGUUUGAUAGGAGCC 0.314 AH0403 SEQ ID NO: 404 GCAAGUUUGAUAGGAGCCAGU SEQ ID NO: 1047 UGGCUCCUAUCAAACUUGCCC SEQ ID NO: 1690 GCAAGUUUGAUAGGAGCCA 0.235 AH0404 SEQ ID NO: 405 CAAGUUUGAUAGGAGCCAGUC SEQ ID NO: 1048 CUGGCUCCUAUCAAACUUGCC SEQ ID NO: 1691 CAAGUUUGAUAGGAGCCAG 0.274 AH0405 SEQ ID NO: 406 AAGUUUGAUAGGAGCCAGUCC SEQ ID NO: 1049 ACUGGCUCCUAUCAAACUUGC SEQ ID NO: 1692 AAGUUUGAUAGGAGCCAGU 0.085 AH0406 SEQ ID NO: 407 UUGAUAGGAGCCAGUCCUUUG SEQ ID NO: 1050 AAGGACUGGCUCCUAUCAAAC SEQ ID NO: 1693 UUGAUAGGAGCCAGUCCUU 0.242 AH0407 SEQ ID NO: 408 UGAUAGGAGCCAGUCCUUUGU SEQ ID NO: 1051 AAAGGACUGGCUCCUAUCAAA SEQ ID NO: 1694 UGAUAGGAGCCAGUCCUUU 0.239 AH0408 SEQ ID NO: 409 GAUAGGAGCCAGUCCUUUGUG SEQ ID NO: 1052 CAAAGGACUGGCUCCUAUCAA SEQ ID NO: 1695 GAUAGGAGCCAGUCCUUUG 0.160 AH0409 SEQ ID NO: 410 AUAGGAGCCAGUCCUUUGUGG SEQ ID NO: 1053 ACAAAGGACUGGCUCCUAUCA SEQ ID NO: 1696 AUAGGAGCCAGUCCUUUGU 0.159 AH0410 SEQ ID NO: 411 AGGAGCCAGUCCUUUGUGGGA SEQ ID NO: 1054 CCACAAAGGACUGGCUCCUAU SEQ ID NO: 1697 AGGAGCCAGUCCUUUGUGG 0.313 AH0411 SEQ ID NO: 412 GGAGCCAGUCCUUUGUGGGAG SEQ ID NO: 1055 CCCACAAAGGACUGGCUCCUA SEQ ID NO: 1698 GGAGCCAGUCCUUUGUGGG 0.232 AH0412 SEQ ID NO: 413 GAGCCAGUCCUUUGUGGGAGA SEQ ID NO: 1056 UCCCACAAAGGACUGGCUCCU SEQ ID NO: 1699 GAGCCAGUCCUUUGUGGGA 0.098 AH0413 SEQ ID NO: 414 AGCCAGUCCUUUGUGGGAGAG SEQ ID NO: 1057 CUCCCACAAAGGACUGGCUCC SEQ ID NO: 1700 AGCCAGUCCUUUGUGGGAG 0.325 AH0414 SEQ ID NO: 415 GCCAGUCCUUUGUGGGAGAGA SEQ ID NO: 1058 UCUCCCACAAAGGACUGGCUC SEQ ID NO: 1701 GCCAGUCCUUUGUGGGAGA 0.109 AH0415 SEQ ID NO: 416 CCAGUCCUUUGUGGGAGAGAU SEQ ID NO: 1059 CUCUCCCACAAAGGACUGGCU SEQ ID NO: 1702 CCAGUCCUUUGUGGGAGAG 0.367 AH0416 SEQ ID NO: 417 CAGUCCUUUGUGGGAGAGAUU SEQ ID NO: 1060 UCUCUCCCACAAAGGACUGGC SEQ ID NO: 1703 CAGUCCUUUGUGGGAGAGA 0.119 AH0417 SEQ ID NO: 418 AGUCCUUUGUGGGAGAGAUUG SEQ ID NO: 1061 AUCUCUCCCACAAAGGACUGG SEQ ID NO: 1704 AGUCCUUUGUGGGAGAGAU 0.074 AH0418 SEQ ID NO: 419 GUCCUUUGUGGGAGAGAUUGG SEQ ID NO: 1062 AAUCUCUCCCACAAAGGACUG SEQ ID NO: 1705 GUCCUUUGUGGGAGAGAUU 0.095 AH0419 SEQ ID NO: 420 UCCUUUGUGGGAGAGAUUGGG SEQ ID NO: 1063 CAAUCUCUCCCACAAAGGACU SEQ ID NO: 1706 UCCUUUGUGGGAGAGAUUG 0.358 AH0420 SEQ ID NO: 421 CCUUUGUGGGAGAGAUUGGGG SEQ ID NO: 1064 CCAAUCUCUCCCACAAAGGAC SEQ ID NO: 1707 CCUUUGUGGGAGAGAUUGG 0.315 AH0421 SEQ ID NO: 422 CUUUGUGGGAGAGAUUGGGGA SEQ ID NO: 1065 CCCAAUCUCUCCCACAAAGGA SEQ ID NO: 1708 CUUUGUGGGAGAGAUUGGG 0.301 AH0422 SEQ ID NO: 423 UUGUGGGAGAGAUUGGGGAUU SEQ ID NO: 1066 UCCCCAAUCUCUCCCACAAAG SEQ ID NO: 1709 UUGUGGGAGAGAUUGGGGA 0.214 AH0423 SEQ ID NO: 424 UGUGGGAGAGAUUGGGGAUUU SEQ ID NO: 1067 AUCCCCAAUCUCUCCCACAAA SEQ ID NO: 1710 UGUGGGAGAGAUUGGGGAU 0.087 AH0424 SEQ ID NO: 425 GUGGGAGAGAUUGGGGAUUUG SEQ ID NO: 1068 AAUCCCCAAUCUCUCCCACAA SEQ ID NO: 1711 GUGGGAGAGAUUGGGGAUU 0.099 AH0425 SEQ ID NO: 426 UGGGAGAGAUUGGGGAUUUGU SEQ ID NO: 1069 AAAUCCCCAAUCUCUCCCACA SEQ ID NO: 1712 UGGGAGAGAUUGGGGAUUU 0.109 AH0426 SEQ ID NO: 427 GGGAGAGAUUGGGGAUUUGUA SEQ ID NO: 1070 CAAAUCCCCAAUCUCUCCCAC SEQ ID NO: 1713 GGGAGAGAUUGGGGAUUUG 0.068 AH0427 SEQ ID NO: 428 GGAGAGAUUGGGGAUUUGUAC SEQ ID NO: 1071 ACAAAUCCCCAAUCUCUCCCA SEQ ID NO: 1714 GGAGAGAUUGGGGAUUUGU 0.071 AH0428 SEQ ID NO: 429 GAGAGAUUGGGGAUUUGUACA SEQ ID NO: 1072 UACAAAUCCCCAAUCUCUCCC SEQ ID NO: 1715 GAGAGAUUGGGGAUUUGUA 0.047 AH0429 SEQ ID NO: 430 AGAGAUUGGGGAUUUGUACAU SEQ ID NO: 1073 GUACAAAUCCCCAAUCUCUCC SEQ ID NO: 1716 AGAGAUUGGGGAUUUGUAC 0.175 AH0430 SEQ ID NO: 431 GAGAUUGGGGAUUUGUACAUG SEQ ID NO: 1074 UGUACAAAUCCCCAAUCUCUC SEQ ID NO: 1717 GAGAUUGGGGAUUUGUACA 0.079 AH0431 SEQ ID NO: 432 AGAUUGGGGAUUUGUACAUGU SEQ ID NO: 1075 AUGUACAAAUCCCCAAUCUCU SEQ ID NO: 1718 AGAUUGGGGAUUUGUACAU 0.391 AH0432 SEQ ID NO: 433 GGGGAUUUGUACAUGUGGGAC SEQ ID NO: 1076 CCCACAUGUACAAAUCCCCAA SEQ ID NO: 1719 GGGGAUUUGUACAUGUGGG 0.154 AH0433 SEQ ID NO: 434 GGGAUUUGUACAUGUGGGACU SEQ ID NO: 1077 UCCCACAUGUACAAAUCCCCA SEQ ID NO: 1720 GGGAUUUGUACAUGUGGGA 0.087 AH0434 SEQ ID NO: 435 GGAUUUGUACAUGUGGGACUC SEQ ID NO: 1078 GUCCCACAUGUACAAAUCCCC SEQ ID NO: 1721 GGAUUUGUACAUGUGGGAC 0.324 AH0435 SEQ ID NO: 436 GAUUUGUACAUGUGGGACUCU SEQ ID NO: 1079 AGUCCCACAUGUACAAAUCCC SEQ ID NO: 1722 GAUUUGUACAUGUGGGACU 0.308 AH0436 SEQ ID NO: 437 UGUACAUGUGGGACUCUGUGC SEQ ID NO: 1080 ACAGAGUCCCACAUGUACAAA SEQ ID NO: 1723 UGUACAUGUGGGACUCUGU 0.210 AH0437 SEQ ID NO: 438 GUACAUGUGGGACUCUGUGCU SEQ ID NO: 1081 CACAGAGUCCCACAUGUACAA SEQ ID NO: 1724 GUACAUGUGGGACUCUGUG 0.384 AH0438 SEQ ID NO: 439 ACAUGUGGGACUCUGUGCUGC SEQ ID NO: 1082 AGCACAGAGUCCCACAUGUAC SEQ ID NO: 1725 ACAUGUGGGACUCUGUGCU 0.269 AH0439 SEQ ID NO: 440 GGGACUCUGUGCUGCCCCCAG SEQ ID NO: 1083 GGGGGCAGCACAGAGUCCCAC SEQ ID NO: 1726 GGGACUCUGUGCUGCCCCC 0.463 AH0440 SEQ ID NO: 441 GGACUCUGUGCUGCCCCCAGA SEQ ID NO: 1084 UGGGGGCAGCACAGAGUCCCA SEQ ID NO: 1727 GGACUCUGUGCUGCCCCCA 0.500 AH0441 SEQ ID NO: 442 ACUCUGUGCUGCCCCCAGAAA SEQ ID NO: 1085 UCUGGGGGCAGCACAGAGUCC SEQ ID NO: 1728 ACUCUGUGCUGCCCCCAGA 0.308 AH0442 SEQ ID NO: 443 CUCUGUGCUGCCCCCAGAAAA SEQ ID NO: 1086 UUCUGGGGGCAGCACAGAGUC SEQ ID NO: 1729 CUCUGUGCUGCCCCCAGAA 0.459 AH0443 SEQ ID NO: 444 CUGUGCUGCCCCCAGAAAAUA SEQ ID NO: 1087 UUUUCUGGGGGCAGCACAGAG SEQ ID NO: 1730 CUGUGCUGCCCCCAGAAAA 0.134 AH0444 SEQ ID NO: 445 UGUGCUGCCCCCAGAAAAUAU SEQ ID NO: 1088 AUUUUCUGGGGGCAGCACAGA SEQ ID NO: 1731 UGUGCUGCCCCCAGAAAAU 0.063 AH0445 SEQ ID NO: 446 GUGCUGCCCCCAGAAAAUAUC SEQ ID NO: 1089 UAUUUUCUGGGGGCAGCACAG SEQ ID NO: 1732 GUGCUGCCCCCAGAAAAUA 0.433 AH0446 SEQ ID NO: 447 GCUGCCCCCAGAAAAUAUCCU SEQ ID NO: 1090 GAUAUUUUCUGGGGGCAGCAC SEQ ID NO: 1733 GCUGCCCCCAGAAAAUAUC 0.414 AH0447 SEQ ID NO: 448 CCCCCAGAAAAUAUCCUGUCU SEQ ID NO: 1091 ACAGGAUAUUUUCUGGGGGCA SEQ ID NO: 1734 CCCCCAGAAAAUAUCCUGU 0.189 AH0448 SEQ ID NO: 449 CCCAGAAAAUAUCCUGUCUGC SEQ ID NO: 1092 AGACAGGAUAUUUUCUGGGGG SEQ ID NO: 1735 CCCAGAAAAUAUCCUGUCU 0.489 AH0449 SEQ ID NO: 450 CCAGAAAAUAUCCUGUCUGCC SEQ ID NO: 1093 CAGACAGGAUAUUUUCUGGGG SEQ ID NO: 1736 CCAGAAAAUAUCCUGUCUG 0.353 AH0450 SEQ ID NO: 451 CAGAAAAUAUCCUGUCUGCCU SEQ ID NO: 1094 GCAGACAGGAUAUUUUCUGGG SEQ ID NO: 1737 CAGAAAAUAUCCUGUCUGC 0.293 AH0451 SEQ ID NO: 452 GAAAAUAUCCUGUCUGCCUAU SEQ ID NO: 1095 AGGCAGACAGGAUAUUUUCUG SEQ ID NO: 1738 GAAAAUAUCCUGUCUGCCU 0.121 AH0452 SEQ ID NO: 453 AAAAUAUCCUGUCUGCCUAUC SEQ ID NO: 1096 UAGGCAGACAGGAUAUUUUCU SEQ ID NO: 1739 AAAAUAUCCUGUCUGCCUA 0.053 AH0453 SEQ ID NO: 454 AAAUAUCCUGUCUGCCUAUCA SEQ ID NO: 1097 AUAGGCAGACAGGAUAUUUUC SEQ ID NO: 1740 AAAUAUCCUGUCUGCCUAU 0.109 AH0454 SEQ ID NO: 455 CCUGUCUGCCUAUCAGGGUAC SEQ ID NO: 1098 ACCCUGAUAGGCAGACAGGAU SEQ ID NO: 1741 CCUGUCUGCCUAUCAGGGU 0.298 AH0455 SEQ ID NO: 456 CUGUCUGCCUAUCAGGGUACC SEQ ID NO: 1099 UACCCUGAUAGGCAGACAGGA SEQ ID NO: 1742 CUGUCUGCCUAUCAGGGUA 0.113 AH0456 SEQ ID NO: 457 GUCUGCCUAUCAGGGUACCCC SEQ ID NO: 1100 GGUACCCUGAUAGGCAGACAG SEQ ID NO: 1743 GUCUGCCUAUCAGGGUACC 0.336 AH0457 SEQ ID NO: 458 UGCCUAUCAGGGUACCCCUCU SEQ ID NO: 1101 AGGGGUACCCUGAUAGGCAGA SEQ ID NO: 1744 UGCCUAUCAGGGUACCCCU 0.251 AH0458 SEQ ID NO: 459 GCCUAUCAGGGUACCCCUCUC SEQ ID NO: 1102 GAGGGGUACCCUGAUAGGCAG SEQ ID NO: 1745 GCCUAUCAGGGUACCCCUC 0.218 AH0459 SEQ ID NO: 460 CCUAUCAGGGUACCCCUCUCC SEQ ID NO: 1103 AGAGGGGUACCCUGAUAGGCA SEQ ID NO: 1746 CCUAUCAGGGUACCCCUCU 0.403 AH0460 SEQ ID NO: 461 CUAUCAGGGUACCCCUCUCCC SEQ ID NO: 1104 GAGAGGGGUACCCUGAUAGGC SEQ ID NO: 1747 CUAUCAGGGUACCCCUCUC 0.104 AH0461 SEQ ID NO: 462 CAGGGUACCCCUCUCCCUGCC SEQ ID NO: 1105 CAGGGAGAGGGGUACCCUGAU SEQ ID NO: 1748 CAGGGUACCCCUCUCCCUG 0.300 AH0462 SEQ ID NO: 463 GGGUACCCCUCUCCCUGCCAA SEQ ID NO: 1106 GGCAGGGAGAGGGGUACCCUG SEQ ID NO: 1749 GGGUACCCCUCUCCCUGCC 0.463 AH0463 SEQ ID NO: 464 GGUACCCCUCUCCCUGCCAAU SEQ ID NO: 1107 UGGCAGGGAGAGGGGUACCCU SEQ ID NO: 1750 GGUACCCCUCUCCCUGCCA 0.476 AH0464 SEQ ID NO: 465 GUACCCCUCUCCCUGCCAAUA SEQ ID NO: 1108 UUGGCAGGGAGAGGGGUACCC SEQ ID NO: 1751 GUACCCCUCUCCCUGCCAA 0.159 AH0465 SEQ ID NO: 466 UACCCCUCUCCCUGCCAAUAU SEQ ID NO: 1109 AUUGGCAGGGAGAGGGGUACC SEQ ID NO: 1752 UACCCCUCUCCCUGCCAAU 0.391 AH0466 SEQ ID NO: 467 CCCCUCUCCCUGCCAAUAUCC SEQ ID NO: 1110 AUAUUGGCAGGGAGAGGGGUA SEQ ID NO: 1753 CCCCUCUCCCUGCCAAUAU 0.389 AH0467 SEQ ID NO: 468 CCCUCUCCCUGCCAAUAUCCU SEQ ID NO: 1111 GAUAUUGGCAGGGAGAGGGGU SEQ ID NO: 1754 CCCUCUCCCUGCCAAUAUC 0.208 AH0468 SEQ ID NO: 469 CUGCCAAUAUCCUGGACUGGC SEQ ID NO: 1112 CAGUCCAGGAUAUUGGCAGGG SEQ ID NO: 1755 CUGCCAAUAUCCUGGACUG 0.333 AH0469 SEQ ID NO: 470 CCAAUAUCCUGGACUGGCAGG SEQ ID NO: 1113 UGCCAGUCCAGGAUAUUGGCA SEQ ID NO: 1756 CCAAUAUCCUGGACUGGCA 0.120 AH0470 SEQ ID NO: 471 CAAUAUCCUGGACUGGCAGGC SEQ ID NO: 1114 CUGCCAGUCCAGGAUAUUGGC SEQ ID NO: 1757 CAAUAUCCUGGACUGGCAG 0.299 AH0471 SEQ ID NO: 472 UCCUGGACUGGCAGGCUCUGA SEQ ID NO: 1115 AGAGCCUGCCAGUCCAGGAUA SEQ ID NO: 1758 UCCUGGACUGGCAGGCUCU 0.386 AH0472 SEQ ID NO: 473 CCUGGACUGGCAGGCUCUGAA SEQ ID NO: 1116 CAGAGCCUGCCAGUCCAGGAU SEQ ID NO: 1759 CCUGGACUGGCAGGCUCUG 0.463 AH0473 SEQ ID NO: 474 CUGGACUGGCAGGCUCUGAAC SEQ ID NO: 1117 UCAGAGCCUGCCAGUCCAGGA SEQ ID NO: 1760 CUGGACUGGCAGGCUCUGA 0.454 AH0474 SEQ ID NO: 475 UGGACUGGCAGGCUCUGAACU SEQ ID NO: 1118 UUCAGAGCCUGCCAGUCCAGG SEQ ID NO: 1761 UGGACUGGCAGGCUCUGAA 0.085 AH0475 SEQ ID NO: 476 GGACUGGCAGGCUCUGAACUA SEQ ID NO: 1119 GUUCAGAGCCUGCCAGUCCAG SEQ ID NO: 1762 GGACUGGCAGGCUCUGAAC 0.383 AH0476 SEQ ID NO: 477 GACUGGCAGGCUCUGAACUAU SEQ ID NO: 1120 AGUUCAGAGCCUGCCAGUCCA SEQ ID NO: 1763 GACUGGCAGGCUCUGAACU 0.308 AH0477 SEQ ID NO: 478 ACUGGCAGGCUCUGAACUAUG SEQ ID NO: 1121 UAGUUCAGAGCCUGCCAGUCC SEQ ID NO: 1764 ACUGGCAGGCUCUGAACUA 0.177 AH0478 SEQ ID NO: 479 CUGGCAGGCUCUGAACUAUGA SEQ ID NO: 1122 AUAGUUCAGAGCCUGCCAGUC SEQ ID NO: 1765 CUGGCAGGCUCUGAACUAU 0.096 AH0479 SEQ ID NO: 480 UGGCAGGCUCUGAACUAUGAA SEQ ID NO: 1123 CAUAGUUCAGAGCCUGCCAGU SEQ ID NO: 1766 UGGCAGGCUCUGAACUAUG 0.306 AH0480 SEQ ID NO: 481 GGCAGGCUCUGAACUAUGAAA SEQ ID NO: 1124 UCAUAGUUCAGAGCCUGCCAG SEQ ID NO: 1767 GGCAGGCUCUGAACUAUGA 0.077 AH0481 SEQ ID NO: 482 GCAGGCUCUGAACUAUGAAAU SEQ ID NO: 1125 UUCAUAGUUCAGAGCCUGCCA SEQ ID NO: 1768 GCAGGCUCUGAACUAUGAA 0.406 AH0482 SEQ ID NO: 483 CAGGCUCUGAACUAUGAAAUC SEQ ID NO: 1126 UUUCAUAGUUCAGAGCCUGCC SEQ ID NO: 1769 CAGGCUCUGAACUAUGAAA 0.133 AH0483 SEQ ID NO: 484 AGGCUCUGAACUAUGAAAUCA SEQ ID NO: 1127 AUUUCAUAGUUCAGAGCCUGC SEQ ID NO: 1770 AGGCUCUGAACUAUGAAAU 0.137 AH0484 SEQ ID NO: 485 GGCUCUGAACUAUGAAAUCAG SEQ ID NO: 1128 GAUUUCAUAGUUCAGAGCCUG SEQ ID NO: 1771 GGCUCUGAACUAUGAAAUC 0.085 AH0485 SEQ ID NO: 486 GCUCUGAACUAUGAAAUCAGA SEQ ID NO: 1129 UGAUUUCAUAGUUCAGAGCCU SEQ ID NO: 1772 GCUCUGAACUAUGAAAUCA 0.217 AH0486 SEQ ID NO: 487 CUCUGAACUAUGAAAUCAGAG SEQ ID NO: 1130 CUGAUUUCAUAGUUCAGAGCC SEQ ID NO: 1773 CUCUGAACUAUGAAAUCAG 0.197 AH0487 SEQ ID NO: 488 UCUGAACUAUGAAAUCAGAGG SEQ ID NO: 1131 UCUGAUUUCAUAGUUCAGAGC SEQ ID NO: 1774 UCUGAACUAUGAAAUCAGA 0.296 AH0488 SEQ ID NO: 489 GAACUAUGAAAUCAGAGGAUA SEQ ID NO: 1132 UCCUCUGAUUUCAUAGUUCAG SEQ ID NO: 1775 GAACUAUGAAAUCAGAGGA 0.128 AH0489 SEQ ID NO: 490 AACUAUGAAAUCAGAGGAUAU SEQ ID NO: 1133 AUCCUCUGAUUUCAUAGUUCA SEQ ID NO: 1776 AACUAUGAAAUCAGAGGAU 0.230 AH0490 SEQ ID NO: 491 ACUAUGAAAUCAGAGGAUAUG SEQ ID NO: 1134 UAUCCUCUGAUUUCAUAGUUC SEQ ID NO: 1777 ACUAUGAAAUCAGAGGAUA 0.125 AH0491 SEQ ID NO: 492 CUAUGAAAUCAGAGGAUAUGU SEQ ID NO: 1135 AUAUCCUCUGAUUUCAUAGUU SEQ ID NO: 1778 CUAUGAAAUCAGAGGAUAU 0.104 AH0492 SEQ ID NO: 493 UAUGAAAUCAGAGGAUAUGUC SEQ ID NO: 1136 CAUAUCCUCUGAUUUCAUAGU SEQ ID NO: 1779 UAUGAAAUCAGAGGAUAUG 0.330 AH0493 SEQ ID NO: 494 UGAAAUCAGAGGAUAUGUCAU SEQ ID NO: 1137 GACAUAUCCUCUGAUUUCAUA SEQ ID NO: 1780 UGAAAUCAGAGGAUAUGUC 0.338 AH0494 SEQ ID NO: 495 GAAAUCAGAGGAUAUGUCAUC SEQ ID NO: 1138 UGACAUAUCCUCUGAUUUCAU SEQ ID NO: 1781 GAAAUCAGAGGAUAUGUCA 0.043 AH0495 SEQ ID NO: 496 AAAUCAGAGGAUAUGUCAUCA SEQ ID NO: 1139 AUGACAUAUCCUCUGAUUUCA SEQ ID NO: 1782 AAAUCAGAGGAUAUGUCAU 0.084 AH0496 SEQ ID NO: 497 AAUCAGAGGAUAUGUCAUCAU SEQ ID NO: 1140 GAUGACAUAUCCUCUGAUUUC SEQ ID NO: 1783 AAUCAGAGGAUAUGUCAUC 0.489 AH0497 SEQ ID NO: 498 CAGAGGAUAUGUCAUCAUCAA SEQ ID NO: 1141 GAUGAUGACAUAUCCUCUGAU SEQ ID NO: 1784 CAGAGGAUAUGUCAUCAUC 0.142 AH0498 SEQ ID NO: 499 AGAGGAUAUGUCAUCAUCAAA SEQ ID NO: 1142 UGAUGAUGACAUAUCCUCUGA SEQ ID NO: 1785 AGAGGAUAUGUCAUCAUCA 0.079 AH0499 SEQ ID NO: 500 GAGGAUAUGUCAUCAUCAAAC SEQ ID NO: 1143 UUGAUGAUGACAUAUCCUCUG SEQ ID NO: 1786 GAGGAUAUGUCAUCAUCAA 0.079 AH0500 SEQ ID NO: 501 AGGAUAUGUCAUCAUCAAACC SEQ ID NO: 1144 UUUGAUGAUGACAUAUCCUCU SEQ ID NO: 1787 AGGAUAUGUCAUCAUCAAA 0.091 AH0501 SEQ ID NO: 502 GGAUAUGUCAUCAUCAAACCC SEQ ID NO: 1145 GUUUGAUGAUGACAUAUCCUC SEQ ID NO: 1788 GGAUAUGUCAUCAUCAAAC 0.062 AH0502 SEQ ID NO: 503 GAUAUGUCAUCAUCAAACCCU SEQ ID NO: 1146 GGUUUGAUGAUGACAUAUCCU SEQ ID NO: 1789 GAUAUGUCAUCAUCAAACC 0.343 AH0503 SEQ ID NO: 504 AUGUCAUCAUCAAACCCUUGG SEQ ID NO: 1147 AAGGGUUUGAUGAUGACAUAU SEQ ID NO: 1790 AUGUCAUCAUCAAACCCUU 0.173 AH0504 SEQ ID NO: 505 CAUCAUCAAACCCUUGGUGUG SEQ ID NO: 1148 CACCAAGGGUUUGAUGAUGAC SEQ ID NO: 1791 CAUCAUCAAACCCUUGGUG 0.442 AH0505 SEQ ID NO: 506 UCAUCAAACCCUUGGUGUGGG SEQ ID NO: 1149 CACACCAAGGGUUUGAUGAUG SEQ ID NO: 1792 UCAUCAAACCCUUGGUGUG 0.355 AH0506 SEQ ID NO: 507 ACCCUUGGUGUGGGUCUGAGG SEQ ID NO: 1150 UCAGACCCACACCAAGGGUUU SEQ ID NO: 1793 ACCCUUGGUGUGGGUCUGA 0.393 AH0507 SEQ ID NO: 508 CCCUUGGUGUGGGUCUGAGGU SEQ ID NO: 1151 CUCAGACCCACACCAAGGGUU SEQ ID NO: 1794 CCCUUGGUGUGGGUCUGAG 0.273 AH0508 SEQ ID NO: 509 CCUUGGUGUGGGUCUGAGGUC SEQ ID NO: 1152 CCUCAGACCCACACCAAGGGU SEQ ID NO: 1795 CCUUGGUGUGGGUCUGAGG 0.137 AH0509 SEQ ID NO: 510 CUUGGUGUGGGUCUGAGGUCU SEQ ID NO: 1153 ACCUCAGACCCACACCAAGGG SEQ ID NO: 1796 CUUGGUGUGGGUCUGAGGU 0.220 AH0510 SEQ ID NO: 511 UGGUGUGGGUCUGAGGUCUUG SEQ ID NO: 1154 AGACCUCAGACCCACACCAAG SEQ ID NO: 1797 UGGUGUGGGUCUGAGGUCU 0.086 AH0511 SEQ ID NO: 512 GGUGUGGGUCUGAGGUCUUGA SEQ ID NO: 1155 AAGACCUCAGACCCACACCAA SEQ ID NO: 1798 GGUGUGGGUCUGAGGUCUU 0.125 AH0512 SEQ ID NO: 513 GUGUGGGUCUGAGGUCUUGAC SEQ ID NO: 1156 CAAGACCUCAGACCCACACCA SEQ ID NO: 1799 GUGUGGGUCUGAGGUCUUG 0.066 AH0513 SEQ ID NO: 514 UGUGGGUCUGAGGUCUUGACU SEQ ID NO: 1157 UCAAGACCUCAGACCCACACC SEQ ID NO: 1800 UGUGGGUCUGAGGUCUUGA 0.104 AH0514 SEQ ID NO: 515 GUGGGUCUGAGGUCUUGACUC SEQ ID NO: 1158 GUCAAGACCUCAGACCCACAC SEQ ID NO: 1801 GUGGGUCUGAGGUCUUGAC 0.098 AH0515 SEQ ID NO: 516 GGGUCUGAGGUCUUGACUCAA SEQ ID NO: 1159 GAGUCAAGACCUCAGACCCAC SEQ ID NO: 1802 GGGUCUGAGGUCUUGACUC 0.136 AH0516 SEQ ID NO: 517 GGUCUGAGGUCUUGACUCAAC SEQ ID NO: 1160 UGAGUCAAGACCUCAGACCCA SEQ ID NO: 1803 GGUCUGAGGUCUUGACUCA 0.072 AH0517 SEQ ID NO: 518 GUCUGAGGUCUUGACUCAACG SEQ ID NO: 1161 UUGAGUCAAGACCUCAGACCC SEQ ID NO: 1804 GUCUGAGGUCUUGACUCAA 0.146 AH0518 SEQ ID NO: 519 CUGAGGUCUUGACUCAACGAG SEQ ID NO: 1162 CGUUGAGUCAAGACCUCAGAC SEQ ID NO: 1805 CUGAGGUCUUGACUCAACG 0.241 AH0519 SEQ ID NO: 520 UGAGGUCUUGACUCAACGAGA SEQ ID NO: 1163 UCGUUGAGUCAAGACCUCAGA SEQ ID NO: 1806 UGAGGUCUUGACUCAACGA 0.087 AH0520 SEQ ID NO: 521 GAGGUCUUGACUCAACGAGAG SEQ ID NO: 1164 CUCGUUGAGUCAAGACCUCAG SEQ ID NO: 1807 GAGGUCUUGACUCAACGAG 0.096 AH0521 SEQ ID NO: 522 AGGUCUUGACUCAACGAGAGC SEQ ID NO: 1165 UCUCGUUGAGUCAAGACCUCA SEQ ID NO: 1808 AGGUCUUGACUCAACGAGA 0.069 AH0522 SEQ ID NO: 523 GGUCUUGACUCAACGAGAGCA SEQ ID NO: 1166 CUCUCGUUGAGUCAAGACCUC SEQ ID NO: 1809 GGUCUUGACUCAACGAGAG 0.077 AH0523 SEQ ID NO: 524 GUCUUGACUCAACGAGAGCAC SEQ ID NO: 1167 GCUCUCGUUGAGUCAAGACCU SEQ ID NO: 1810 GUCUUGACUCAACGAGAGC 0.218 AH0524 SEQ ID NO: 525 UCUUGACUCAACGAGAGCACU SEQ ID NO: 1168 UGCUCUCGUUGAGUCAAGACC SEQ ID NO: 1811 UCUUGACUCAACGAGAGCA 0.125 AH0525 SEQ ID NO: 526 CUUGACUCAACGAGAGCACUU SEQ ID NO: 1169 GUGCUCUCGUUGAGUCAAGAC SEQ ID NO: 1812 CUUGACUCAACGAGAGCAC 0.195 AH0526 SEQ ID NO: 527 UUGACUCAACGAGAGCACUUG SEQ ID NO: 1170 AGUGCUCUCGUUGAGUCAAGA SEQ ID NO: 1813 UUGACUCAACGAGAGCACU 0.101 AH0527 SEQ ID NO: 528 UGACUCAACGAGAGCACUUGA SEQ ID NO: 1171 AAGUGCUCUCGUUGAGUCAAG SEQ ID NO: 1814 UGACUCAACGAGAGCACUU 0.189 AH0528 SEQ ID NO: 529 GACUCAACGAGAGCACUUGAA SEQ ID NO: 1172 CAAGUGCUCUCGUUGAGUCAA SEQ ID NO: 1815 GACUCAACGAGAGCACUUG 0.090 AH0529 SEQ ID NO: 530 ACUCAACGAGAGCACUUGAAA SEQ ID NO: 1173 UCAAGUGCUCUCGUUGAGUCA SEQ ID NO: 1816 ACUCAACGAGAGCACUUGA 0.104 AH0530 SEQ ID NO: 531 CUCAACGAGAGCACUUGAAAA SEQ ID NO: 1174 UUCAAGUGCUCUCGUUGAGUC SEQ ID NO: 1817 CUCAACGAGAGCACUUGAA 0.107 AH0531 SEQ ID NO: 532 UCAACGAGAGCACUUGAAAAU SEQ ID NO: 1175 UUUCAAGUGCUCUCGUUGAGU SEQ ID NO: 1818 UCAACGAGAGCACUUGAAA 0.063 AH0532 SEQ ID NO: 533 CAACGAGAGCACUUGAAAAUG SEQ ID NO: 1176 UUUUCAAGUGCUCUCGUUGAG SEQ ID NO: 1819 CAACGAGAGCACUUGAAAA 0.066 AH0533 SEQ ID NO: 534 AACGAGAGCACUUGAAAAUGA SEQ ID NO: 1177 AUUUUCAAGUGCUCUCGUUGA SEQ ID NO: 1820 AACGAGAGCACUUGAAAAU 0.054 AH0534 SEQ ID NO: 535 ACGAGAGCACUUGAAAAUGAA SEQ ID NO: 1178 CAUUUUCAAGUGCUCUCGUUG SEQ ID NO: 1821 ACGAGAGCACUUGAAAAUG 0.073 AH0535 SEQ ID NO: 536 CGAGAGCACUUGAAAAUGAAA SEQ ID NO: 1179 UCAUUUUCAAGUGCUCUCGUU SEQ ID NO: 1822 CGAGAGCACUUGAAAAUGA 0.026 AH0536 SEQ ID NO: 537 GAGAGCACUUGAAAAUGAAAU SEQ ID NO: 1180 UUCAUUUUCAAGUGCUCUCGU SEQ ID NO: 1823 GAGAGCACUUGAAAAUGAA 0.031 AH0537 SEQ ID NO: 538 AGAGCACUUGAAAAUGAAAUG SEQ ID NO: 1181 UUUCAUUUUCAAGUGCUCUCG SEQ ID NO: 1824 AGAGCACUUGAAAAUGAAA 0.059 AH0538 SEQ ID NO: 539 GAGCACUUGAAAAUGAAAUGA SEQ ID NO: 1182 AUUUCAUUUUCAAGUGCUCUC SEQ ID NO: 1825 GAGCACUUGAAAAUGAAAU 0.054 AH0539 SEQ ID NO: 540 AGCACUUGAAAAUGAAAUGAC SEQ ID NO: 1183 CAUUUCAUUUUCAAGUGCUCU SEQ ID NO: 1826 AGCACUUGAAAAUGAAAUG 0.032 AH0540 SEQ ID NO: 541 GCACUUGAAAAUGAAAUGACU SEQ ID NO: 1184 UCAUUUCAUUUUCAAGUGCUC SEQ ID NO: 1827 GCACUUGAAAAUGAAAUGA 0.074 AH0541 SEQ ID NO: 542 CACUUGAAAAUGAAAUGACUG SEQ ID NO: 1185 GUCAUUUCAUUUUCAAGUGCU SEQ ID NO: 1828 CACUUGAAAAUGAAAUGAC 0.204 AH0542 SEQ ID NO: 543 ACUUGAAAAUGAAAUGACUGU SEQ ID NO: 1186 AGUCAUUUCAUUUUCAAGUGC SEQ ID NO: 1829 ACUUGAAAAUGAAAUGACU 0.103 AH0543 SEQ ID NO: 544 CUUGAAAAUGAAAUGACUGUC SEQ ID NO: 1187 CAGUCAUUUCAUUUUCAAGUG SEQ ID NO: 1830 CUUGAAAAUGAAAUGACUG 0.121 AH0544 SEQ ID NO: 545 UUGAAAAUGAAAUGACUGUCU SEQ ID NO: 1188 ACAGUCAUUUCAUUUUCAAGU SEQ ID NO: 1831 UUGAAAAUGAAAUGACUGU 0.201 AH0545 SEQ ID NO: 546 UGAAAAUGAAAUGACUGUCUA SEQ ID NO: 1189 GACAGUCAUUUCAUUUUCAAG SEQ ID NO: 1832 UGAAAAUGAAAUGACUGUC 0.445 AH0546 SEQ ID NO: 547 GAAAAUGAAAUGACUGUCUAA SEQ ID NO: 1190 AGACAGUCAUUUCAUUUUCAA SEQ ID NO: 1833 GAAAAUGAAAUGACUGUCU 0.068 AH0547 SEQ ID NO: 548 AAAAUGAAAUGACUGUCUAAG SEQ ID NO: 1191 UAGACAGUCAUUUCAUUUUCA SEQ ID NO: 1834 AAAAUGAAAUGACUGUCUA 0.053 AH0548 SEQ ID NO: 549 AAAUGAAAUGACUGUCUAAGA SEQ ID NO: 1192 UUAGACAGUCAUUUCAUUUUC SEQ ID NO: 1835 AAAUGAAAUGACUGUCUAA 0.073 AH0549 SEQ ID NO: 550 AAUGAAAUGACUGUCUAAGAG SEQ ID NO: 1193 CUUAGACAGUCAUUUCAUUUU SEQ ID NO: 1836 AAUGAAAUGACUGUCUAAG 0.365 AH0550 SEQ ID NO: 551 AUGAAAUGACUGUCUAAGAGA SEQ ID NO: 1194 UCUUAGACAGUCAUUUCAUUU SEQ ID NO: 1837 AUGAAAUGACUGUCUAAGA 0.395 AH0551 SEQ ID NO: 552 UGAAAUGACUGUCUAAGAGAU SEQ ID NO: 1195 CUCUUAGACAGUCAUUUCAUU SEQ ID NO: 1838 UGAAAUGACUGUCUAAGAG 0.471 AH0552 SEQ ID NO: 553 GAAAUGACUGUCUAAGAGAUC SEQ ID NO: 1196 UCUCUUAGACAGUCAUUUCAU SEQ ID NO: 1839 GAAAUGACUGUCUAAGAGA 0.077 AH0553 SEQ ID NO: 554 AAAUGACUGUCUAAGAGAUCU SEQ ID NO: 1197 AUCUCUUAGACAGUCAUUUCA SEQ ID NO: 1840 AAAUGACUGUCUAAGAGAU 0.161 AH0554 SEQ ID NO: 555 AUGACUGUCUAAGAGAUCUGG SEQ ID NO: 1198 AGAUCUCUUAGACAGUCAUUU SEQ ID NO: 1841 AUGACUGUCUAAGAGAUCU 0.244 AH0555 SEQ ID NO: 556 UGACUGUCUAAGAGAUCUGGU SEQ ID NO: 1199 CAGAUCUCUUAGACAGUCAUU SEQ ID NO: 1842 UGACUGUCUAAGAGAUCUG 0.390 AH0556 SEQ ID NO: 557 GACUGUCUAAGAGAUCUGGUC SEQ ID NO: 1200 CCAGAUCUCUUAGACAGUCAU SEQ ID NO: 1843 GACUGUCUAAGAGAUCUGG 0.143 AH0557 SEQ ID NO: 558 ACUGUCUAAGAGAUCUGGUCA SEQ ID NO: 1201 ACCAGAUCUCUUAGACAGUCA SEQ ID NO: 1844 ACUGUCUAAGAGAUCUGGU 0.202 AH0558 SEQ ID NO: 559 CUGUCUAAGAGAUCUGGUCAA SEQ ID NO: 1202 GACCAGAUCUCUUAGACAGUC SEQ ID NO: 1845 CUGUCUAAGAGAUCUGGUC 0.119 AH0559 SEQ ID NO: 560 UGUCUAAGAGAUCUGGUCAAA SEQ ID NO: 1203 UGACCAGAUCUCUUAGACAGU SEQ ID NO: 1846 UGUCUAAGAGAUCUGGUCA 0.121 AH0560 SEQ ID NO: 561 GUCUAAGAGAUCUGGUCAAAG SEQ ID NO: 1204 UUGACCAGAUCUCUUAGACAG SEQ ID NO: 1847 GUCUAAGAGAUCUGGUCAA 0.053 AH0561 SEQ ID NO: 562 UCUAAGAGAUCUGGUCAAAGC SEQ ID NO: 1205 UUUGACCAGAUCUCUUAGACA SEQ ID NO: 1848 UCUAAGAGAUCUGGUCAAA 0.081 AH0562 SEQ ID NO: 563 CUAAGAGAUCUGGUCAAAGCA SEQ ID NO: 1206 CUUUGACCAGAUCUCUUAGAC SEQ ID NO: 1849 CUAAGAGAUCUGGUCAAAG 0.051 AH0563 SEQ ID NO: 564 UAAGAGAUCUGGUCAAAGCAA SEQ ID NO: 1207 GCUUUGACCAGAUCUCUUAGA SEQ ID NO: 1850 UAAGAGAUCUGGUCAAAGC 0.363 AH0564 SEQ ID NO: 565 AAGAGAUCUGGUCAAAGCAAC SEQ ID NO: 1208 UGCUUUGACCAGAUCUCUUAG SEQ ID NO: 1851 AAGAGAUCUGGUCAAAGCA 0.053 AH0565 SEQ ID NO: 566 AGAGAUCUGGUCAAAGCAACU SEQ ID NO: 1209 UUGCUUUGACCAGAUCUCUUA SEQ ID NO: 1852 AGAGAUCUGGUCAAAGCAA 0.091 AH0566 SEQ ID NO: 567 GAGAUCUGGUCAAAGCAACUG SEQ ID NO: 1210 GUUGCUUUGACCAGAUCUCUU SEQ ID NO: 1853 GAGAUCUGGUCAAAGCAAC 0.074 AH0567 SEQ ID NO: 568 AGAUCUGGUCAAAGCAACUGG SEQ ID NO: 1211 AGUUGCUUUGACCAGAUCUCU SEQ ID NO: 1854 AGAUCUGGUCAAAGCAACU 0.096 AH0568 SEQ ID NO: 569 GAUCUGGUCAAAGCAACUGGA SEQ ID NO: 1212 CAGUUGCUUUGACCAGAUCUC SEQ ID NO: 1855 GAUCUGGUCAAAGCAACUG 0.118 AH0569 SEQ ID NO: 570 AUCUGGUCAAAGCAACUGGAU SEQ ID NO: 1213 CCAGUUGCUUUGACCAGAUCU SEQ ID NO: 1856 AUCUGGUCAAAGCAACUGG 0.225 AH0570 SEQ ID NO: 571 UCUGGUCAAAGCAACUGGAUA SEQ ID NO: 1214 UCCAGUUGCUUUGACCAGAUC SEQ ID NO: 1857 UCUGGUCAAAGCAACUGGA 0.105 AH0571 SEQ ID NO: 572 CUGGUCAAAGCAACUGGAUAC SEQ ID NO: 1215 AUCCAGUUGCUUUGACCAGAU SEQ ID NO: 1858 CUGGUCAAAGCAACUGGAU 0.160 AH0572 SEQ ID NO: 573 UGGUCAAAGCAACUGGAUACU SEQ ID NO: 1216 UAUCCAGUUGCUUUGACCAGA SEQ ID NO: 1859 UGGUCAAAGCAACUGGAUA 0.093 AH0573 SEQ ID NO: 574 GGUCAAAGCAACUGGAUACUA SEQ ID NO: 1217 GUAUCCAGUUGCUUUGACCAG SEQ ID NO: 1860 GGUCAAAGCAACUGGAUAC 0.118 AH0574 SEQ ID NO: 575 GUCAAAGCAACUGGAUACUAG SEQ ID NO: 1218 AGUAUCCAGUUGCUUUGACCA SEQ ID NO: 1861 GUCAAAGCAACUGGAUACU 0.131 AH0575 SEQ ID NO: 576 UCAAAGCAACUGGAUACUAGA SEQ ID NO: 1219 UAGUAUCCAGUUGCUUUGACC SEQ ID NO: 1862 UCAAAGCAACUGGAUACUA 0.094 AH0576 SEQ ID NO: 577 CAAAGCAACUGGAUACUAGAU SEQ ID NO: 1220 CUAGUAUCCAGUUGCUUUGAC SEQ ID NO: 1863 CAAAGCAACUGGAUACUAG 0.122 AH0577 SEQ ID NO: 578 AAAGCAACUGGAUACUAGAUC SEQ ID NO: 1221 UCUAGUAUCCAGUUGCUUUGA SEQ ID NO: 1864 AAAGCAACUGGAUACUAGA 0.089 AH0578 SEQ ID NO: 579 AAGCAACUGGAUACUAGAUCU SEQ ID NO: 1222 AUCUAGUAUCCAGUUGCUUUG SEQ ID NO: 1865 AAGCAACUGGAUACUAGAU 0.156 AH0579 SEQ ID NO: 580 AGCAACUGGAUACUAGAUCUU SEQ ID NO: 1223 GAUCUAGUAUCCAGUUGCUUU SEQ ID NO: 1866 AGCAACUGGAUACUAGAUC 0.248 AH0580 SEQ ID NO: 581 GCAACUGGAUACUAGAUCUUA SEQ ID NO: 1224 AGAUCUAGUAUCCAGUUGCUU SEQ ID NO: 1867 GCAACUGGAUACUAGAUCU 0.089 AH0581 SEQ ID NO: 582 CAACUGGAUACUAGAUCUUAC SEQ ID NO: 1225 AAGAUCUAGUAUCCAGUUGCU SEQ ID NO: 1868 CAACUGGAUACUAGAUCUU 0.067 AH0582 SEQ ID NO: 583 AACUGGAUACUAGAUCUUACA SEQ ID NO: 1226 UAAGAUCUAGUAUCCAGUUGC SEQ ID NO: 1869 AACUGGAUACUAGAUCUUA 0.101 AH0583 SEQ ID NO: 584 ACUGGAUACUAGAUCUUACAU SEQ ID NO: 1227 GUAAGAUCUAGUAUCCAGUUG SEQ ID NO: 1870 ACUGGAUACUAGAUCUUAC 0.096 AH0584 SEQ ID NO: 585 CUGGAUACUAGAUCUUACAUC SEQ ID NO: 1228 UGUAAGAUCUAGUAUCCAGUU SEQ ID NO: 1871 CUGGAUACUAGAUCUUACA 0.075 AH0585 SEQ ID NO: 586 UGGAUACUAGAUCUUACAUCU SEQ ID NO: 1229 AUGUAAGAUCUAGUAUCCAGU SEQ ID NO: 1872 UGGAUACUAGAUCUUACAU 0.115 AH0586 SEQ ID NO: 587 GGAUACUAGAUCUUACAUCUG SEQ ID NO: 1230 GAUGUAAGAUCUAGUAUCCAG SEQ ID NO: 1873 GGAUACUAGAUCUUACAUC 0.087 AH0587 SEQ ID NO: 588 GAUACUAGAUCUUACAUCUGC SEQ ID NO: 1231 AGAUGUAAGAUCUAGUAUCCA SEQ ID NO: 1874 GAUACUAGAUCUUACAUCU 0.069 AH0588 SEQ ID NO: 589 AUACUAGAUCUUACAUCUGCA SEQ ID NO: 1232 CAGAUGUAAGAUCUAGUAUCC SEQ ID NO: 1875 AUACUAGAUCUUACAUCUG 0.105 AH0589 SEQ ID NO: 590 ACUAGAUCUUACAUCUGCAGC SEQ ID NO: 1233 UGCAGAUGUAAGAUCUAGUAU SEQ ID NO: 1876 ACUAGAUCUUACAUCUGCA 0.069 AH0590 SEQ ID NO: 591 CUAGAUCUUACAUCUGCAGCU SEQ ID NO: 1234 CUGCAGAUGUAAGAUCUAGUA SEQ ID NO: 1877 CUAGAUCUUACAUCUGCAG 0.091 AH0591 SEQ ID NO: 592 AGAUCUUACAUCUGCAGCUCU SEQ ID NO: 1235 AGCUGCAGAUGUAAGAUCUAG SEQ ID NO: 1878 AGAUCUUACAUCUGCAGCU 0.112 AH0592 SEQ ID NO: 593 GAUCUUACAUCUGCAGCUCUU SEQ ID NO: 1236 GAGCUGCAGAUGUAAGAUCUA SEQ ID NO: 1879 GAUCUUACAUCUGCAGCUC 0.096 AH0593 SEQ ID NO: 594 AUCUUACAUCUGCAGCUCUUU SEQ ID NO: 1237 AGAGCUGCAGAUGUAAGAUCU SEQ ID NO: 1880 AUCUUACAUCUGCAGCUCU 0.089 AH0594 SEQ ID NO: 595 UCUUACAUCUGCAGCUCUUUC SEQ ID NO: 1238 AAGAGCUGCAGAUGUAAGAUC SEQ ID NO: 1881 UCUUACAUCUGCAGCUCUU 0.083 AH0595 SEQ ID NO: 596 CUUACAUCUGCAGCUCUUUCU SEQ ID NO: 1239 AAAGAGCUGCAGAUGUAAGAU SEQ ID NO: 1882 CUUACAUCUGCAGCUCUUU 0.058 AH0596 SEQ ID NO: 597 UUACAUCUGCAGCUCUUUCUU SEQ ID NO: 1240 GAAAGAGCUGCAGAUGUAAGA SEQ ID NO: 1883 UUACAUCUGCAGCUCUUUC 0.110 AH0597 SEQ ID NO: 598 UACAUCUGCAGCUCUUUCUUC SEQ ID NO: 1241 AGAAAGAGCUGCAGAUGUAAG SEQ ID NO: 1884 UACAUCUGCAGCUCUUUCU 0.168 AH0598 SEQ ID NO: 599 ACAUCUGCAGCUCUUUCUUCU SEQ ID NO: 1242 AAGAAAGAGCUGCAGAUGUAA SEQ ID NO: 1885 ACAUCUGCAGCUCUUUCUU 0.083 AH0599 SEQ ID NO: 600 CAUCUGCAGCUCUUUCUUCUU SEQ ID NO: 1243 GAAGAAAGAGCUGCAGAUGUA SEQ ID NO: 1886 CAUCUGCAGCUCUUUCUUC 0.072 AH0600 SEQ ID NO: 601 AUCUGCAGCUCUUUCUUCUUU SEQ ID NO: 1244 AGAAGAAAGAGCUGCAGAUGU SEQ ID NO: 1887 AUCUGCAGCUCUUUCUUCU 0.072 AH0601 SEQ ID NO: 602 UCUGCAGCUCUUUCUUCUUUG SEQ ID NO: 1245 AAGAAGAAAGAGCUGCAGAUG SEQ ID NO: 1888 UCUGCAGCUCUUUCUUCUU 0.086 AH0602 SEQ ID NO: 603 CUGCAGCUCUUUCUUCUUUGA SEQ ID NO: 1246 AAAGAAGAAAGAGCUGCAGAU SEQ ID NO: 1889 CUGCAGCUCUUUCUUCUUU 0.097 AH0603 SEQ ID NO: 604 UGCAGCUCUUUCUUCUUUGAA SEQ ID NO: 1247 CAAAGAAGAAAGAGCUGCAGA SEQ ID NO: 1890 UGCAGCUCUUUCUUCUUUG 0.096 AH0604 SEQ ID NO: 605 GCAGCUCUUUCUUCUUUGAAU SEQ ID NO: 1248 UCAAAGAAGAAAGAGCUGCAG SEQ ID NO: 1891 GCAGCUCUUUCUUCUUUGA 0.059 AH0605 SEQ ID NO: 606 CAGCUCUUUCUUCUUUGAAUU SEQ ID NO: 1249 UUCAAAGAAGAAAGAGCUGCA SEQ ID NO: 1892 CAGCUCUUUCUUCUUUGAA 0.054 AH0606 SEQ ID NO: 607 AGCUCUUUCUUCUUUGAAUUU SEQ ID NO: 1250 AUUCAAAGAAGAAAGAGCUGC SEQ ID NO: 1893 AGCUCUUUCUUCUUUGAAU 0.053 AH0607 SEQ ID NO: 608 GCUCUUUCUUCUUUGAAUUUC SEQ ID NO: 1251 AAUUCAAAGAAGAAAGAGCUG SEQ ID NO: 1894 GCUCUUUCUUCUUUGAAUU 0.057 AH0608 SEQ ID NO: 609 CUCUUUCUUCUUUGAAUUUCC SEQ ID NO: 1252 AAAUUCAAAGAAGAAAGAGCU SEQ ID NO: 1895 CUCUUUCUUCUUUGAAUUU 0.068 AH0609 SEQ ID NO: 610 UCUUUCUUCUUUGAAUUUCCU SEQ ID NO: 1253 GAAAUUCAAAGAAGAAAGAGC SEQ ID NO: 1896 UCUUUCUUCUUUGAAUUUC 0.184 AH0610 SEQ ID NO: 611 CUUUCUUCUUUGAAUUUCCUA SEQ ID NO: 1254 GGAAAUUCAAAGAAGAAAGAG SEQ ID NO: 1897 CUUUCUUCUUUGAAUUUCC 0.079 AH0611 SEQ ID NO: 612 UUUCUUCUUUGAAUUUCCUAU SEQ ID NO: 1255 AGGAAAUUCAAAGAAGAAAGA SEQ ID NO: 1898 UUUCUUCUUUGAAUUUCCU 0.124 AH0612 SEQ ID NO: 613 UUCUUCUUUGAAUUUCCUAUC SEQ ID NO: 1256 UAGGAAAUUCAAAGAAGAAAG SEQ ID NO: 1899 UUCUUCUUUGAAUUUCCUA 0.212 AH0613 SEQ ID NO: 614 UCUUCUUUGAAUUUCCUAUCU SEQ ID NO: 1257 AUAGGAAAUUCAAAGAAGAAA SEQ ID NO: 1900 UCUUCUUUGAAUUUCCUAU 0.259 AH0614 SEQ ID NO: 615 UUCUUUGAAUUUCCUAUCUGU SEQ ID NO: 1258 AGAUAGGAAAUUCAAAGAAGA SEQ ID NO: 1901 UUCUUUGAAUUUCCUAUCU 0.171 AH0615 SEQ ID NO: 616 UCUUUGAAUUUCCUAUCUGUA SEQ ID NO: 1259 CAGAUAGGAAAUUCAAAGAAG SEQ ID NO: 1902 UCUUUGAAUUUCCUAUCUG 0.194 AH0616 SEQ ID NO: 617 CUUUGAAUUUCCUAUCUGUAU SEQ ID NO: 1260 ACAGAUAGGAAAUUCAAAGAA SEQ ID NO: 1903 CUUUGAAUUUCCUAUCUGU 0.073 AH0617 SEQ ID NO: 618 UUUGAAUUUCCUAUCUGUAUG SEQ ID NO: 1261 UACAGAUAGGAAAUUCAAAGA SEQ ID NO: 1904 UUUGAAUUUCCUAUCUGUA 0.072 AH0618 SEQ ID NO: 619 UUGAAUUUCCUAUCUGUAUGU SEQ ID NO: 1262 AUACAGAUAGGAAAUUCAAAG SEQ ID NO: 1905 UUGAAUUUCCUAUCUGUAU 0.104 AH0619 SEQ ID NO: 620 UGAAUUUCCUAUCUGUAUGUC SEQ ID NO: 1263 CAUACAGAUAGGAAAUUCAAA SEQ ID NO: 1906 UGAAUUUCCUAUCUGUAUG 0.151 AH0620 SEQ ID NO: 621 GAAUUUCCUAUCUGUAUGUCU SEQ ID NO: 1264 ACAUACAGAUAGGAAAUUCAA SEQ ID NO: 1907 GAAUUUCCUAUCUGUAUGU 0.066 AH0621 SEQ ID NO: 622 AUUUCCUAUCUGUAUGUCUGC SEQ ID NO: 1265 AGACAUACAGAUAGGAAAUUC SEQ ID NO: 1908 AUUUCCUAUCUGUAUGUCU 0.280 AH0622 SEQ ID NO: 623 UUUCCUAUCUGUAUGUCUGCC SEQ ID NO: 1266 CAGACAUACAGAUAGGAAAUU SEQ ID NO: 1909 UUUCCUAUCUGUAUGUCUG 0.222 AH0623 SEQ ID NO: 624 UUCCUAUCUGUAUGUCUGCCU SEQ ID NO: 1267 GCAGACAUACAGAUAGGAAAU SEQ ID NO: 1910 UUCCUAUCUGUAUGUCUGC 0.474 AH0624 SEQ ID NO: 625 UCCUAUCUGUAUGUCUGCCUA SEQ ID NO: 1268 GGCAGACAUACAGAUAGGAAA SEQ ID NO: 1911 UCCUAUCUGUAUGUCUGCC 0.494 AH0625 SEQ ID NO: 626 CCUAUCUGUAUGUCUGCCUAA SEQ ID NO: 1269 AGGCAGACAUACAGAUAGGAA SEQ ID NO: 1912 CCUAUCUGUAUGUCUGCCU 0.088 AH0626 SEQ ID NO: 627 CUAUCUGUAUGUCUGCCUAAU SEQ ID NO: 1270 UAGGCAGACAUACAGAUAGGA SEQ ID NO: 1913 CUAUCUGUAUGUCUGCCUA 0.073 AH0627 SEQ ID NO: 628 UAUCUGUAUGUCUGCCUAAUU SEQ ID NO: 1271 UUAGGCAGACAUACAGAUAGG SEQ ID NO: 1914 UAUCUGUAUGUCUGCCUAA 0.114 AH0628 SEQ ID NO: 629 AUCUGUAUGUCUGCCUAAUUA SEQ ID NO: 1272 AUUAGGCAGACAUACAGAUAG SEQ ID NO: 1915 AUCUGUAUGUCUGCCUAAU 0.073 AH0629 SEQ ID NO: 630 UCUGUAUGUCUGCCUAAUUAA SEQ ID NO: 1273 AAUUAGGCAGACAUACAGAUA SEQ ID NO: 1916 UCUGUAUGUCUGCCUAAUU 0.132 AH0630 SEQ ID NO: 631 CUGUAUGUCUGCCUAAUUAAA SEQ ID NO: 1274 UAAUUAGGCAGACAUACAGAU SEQ ID NO: 1917 CUGUAUGUCUGCCUAAUUA 0.051 AH0631 SEQ ID NO: 632 UGUAUGUCUGCCUAAUUAAAA SEQ ID NO: 1275 UUAAUUAGGCAGACAUACAGA SEQ ID NO: 1918 UGUAUGUCUGCCUAAUUAA 0.109 AH0632 SEQ ID NO: 633 GUAUGUCUGCCUAAUUAAAAA SEQ ID NO: 1276 UUUAAUUAGGCAGACAUACAG SEQ ID NO: 1919 GUAUGUCUGCCUAAUUAAA 0.091 AH0633 SEQ ID NO: 634 UAUGUCUGCCUAAUUAAAAAA SEQ ID NO: 1277 UUUUAAUUAGGCAGACAUACA SEQ ID NO: 1920 UAUGUCUGCCUAAUUAAAA 0.083 AH0634 SEQ ID NO: 635 AUGUCUGCCUAAUUAAAAAAA SEQ ID NO: 1278 UUUUUAAUUAGGCAGACAUAC SEQ ID NO: 1921 AUGUCUGCCUAAUUAAAAA 0.081 AH0635 SEQ ID NO: 636 UGUCUGCCUAAUUAAAAAAAU SEQ ID NO: 1279 UUUUUUAAUUAGGCAGACAUA SEQ ID NO: 1922 UGUCUGCCUAAUUAAAAAA 0.113 AH0636 SEQ ID NO: 637 GUCUGCCUAAUUAAAAAAAUA SEQ ID NO: 1280 UUUUUUUAAUUAGGCAGACAU SEQ ID NO: 1923 GUCUGCCUAAUUAAAAAAA 0.179 AH0637 SEQ ID NO: 638 UCUGCCUAAUUAAAAAAAUAU SEQ ID NO: 1281 AUUUUUUUAAUUAGGCAGACA SEQ ID NO: 1924 UCUGCCUAAUUAAAAAAAU 0.113 AH0638 SEQ ID NO: 639 CUGCCUAAUUAAAAAAAUAUA SEQ ID NO: 1282 UAUUUUUUUAAUUAGGCAGAC SEQ ID NO: 1925 CUGCCUAAUUAAAAAAAUA 0.043 AH0639 SEQ ID NO: 640 UGCCUAAUUAAAAAAAUAUAU SEQ ID NO: 1283 AUAUUUUUUUAAUUAGGCAGA SEQ ID NO: 1926 UGCCUAAUUAAAAAAAUAU 0.151 AH0640 SEQ ID NO: 641 GCCUAAUUAAAAAAAUAUAUA SEQ ID NO: 1284 UAUAUUUUUUUAAUUAGGCAG SEQ ID NO: 1927 GCCUAAUUAAAAAAAUAUA 0.191 AH0641 SEQ ID NO: 642 CCUAAUUAAAAAAAUAUAUAU SEQ ID NO: 1285 AUAUAUUUUUUUAAUUAGGCA SEQ ID NO: 1928 CCUAAUUAAAAAAAUAUAU 0.361 AH0642 SEQ ID NO: 643 CUAAUUAAAAAAAUAUAUAUU SEQ ID NO: 1286 UAUAUAUUUUUUUAAUUAGGC SEQ ID NO: 1929 CUAAUUAAAAAAAUAUAUA 0.287 AH0643 SEQ ID NO: 644 UAAAAAAAUAUAUAUUGUAUU SEQ ID NO: 1287 UACAAUAUAUAUUUUUUUAAU SEQ ID NO: 1930 UAAAAAAAUAUAUAUUGUA 0.376

Note that, the full length base sequence of the 2nd strand cDNA of APCS is shown in Table 2.

TABLE 2 SEQ gggcatgaatatcagacgctagggggacagccactgtgttgtctgc ID taccctcatcctggtcactgcttctgctataacagccctaggccag NO: gaatatgaacaagccgctgctttggatctctgtcctcaccagcctc 1 ctggaagcctttgctcacacagacctcagtgggaaggtgtttgtat ttcctagagaatctgttactgatcatgtaaacttgatcacaccgct ggagaagcctctacagaactttaccttgtgttttcgagcctatagt gatctctctcgtgcctacagcctcttctcctacaatacccaaggca gggataatgagctactagtttataaagaaagagttggagagtatag tctatacattggaagacacaaagttacatccaaagttatcgaaaag ttcccggctccagtgcacatctgtgtgagctgggagtcctcatcag gtattgctgaattttggatcaatgggacacctttggtgaaaaaggg tctgcgacagggttactttgtagaagctcagcccaagattgtcctg gggcaggaacaggattcctatgggggcaagtttgataggagccagt cctttgtgggagagattggggatttgtacatgtgggactctgtgct gcccccagaaaatatcctgtctgcctatcagggtacccctctccct gccaatatcctggactggcaggctctgaactatgaaatcagaggat atgtcatcatcaaacccttggtgtgggtctgaggtcttgactcaac gagagcacttgaaaatgaaatgactgtctaagagatctggtcaaag caactggatactagatcttacatctgcagctctttcttctttgaat ttcctatctgtatgtctgcctaattaaaaaaatatatattgtatta tgctacctgcaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa

Example 3 Knockdown Activity of Chemically Modified Double-Stranded Nucleic Acid

Synthesis of sense-strand nucleic acids consisting of ribonucleotides represented by SEQ ID NOs: 1931 to 1974, and antisense-strand nucleic acids consisting of ribonucleotides represented by SEQ ID NOs: 1975 to 2018 were outsourced to Gene Design, Inc., and double-stranded nucleic acids were prepared by annealing them (sense-strands represented by SEQ ID NO: n (n=1931 to 1974) and the antisense-strands represented by SEQ ID NO: [n+44] are paired).

The final concentration of each of the double-stranded nucleic acids that was synthesized was set at 1 nM or 0.1 nM. The same operation as in Example 2 was repeated except that each of the double-stranded nucleic acids was introduced in RMG-1 cells and culture was carried out for 24 hours. The relative expression levels of APCS mRNAs were calculated. This experiment was repeated 4 times and median values of the relative expression levels of APCS mRNAs are shown in Table 3. In Table 3, N(M) represents 2′-O-methyl-RNA and N(F) represents 2′-F-RNA, wherein N represents A, C, G or U. For convenience sake, Table 3 will be separately shown as follows.

TABLE 3  APCS APCS Double relative relative stranded expression expression nucleic Sense strand sequence Antisense strand sequence level level acid No. SEQ ID NO: (5′--->3′) SEQ ID NO: (5′--->3′) (1 nM) (0.1 nM) AH0644 SEQ ID NO: U(F)A(M)C(F)C(M)U(F)U(M)G(F)U(M)G(F)U(M)U SEQ ID NO: U(F)A(M)G(F)G(M)C(F)U(M)C(F)G(M)A(F)A(M)A(M)A 0.057 0.098 1931 (F)U(F)U(M)C(F)G(M)A(F)G(M)C(F)C(M)U(F)A(M) 1975 (F)C(M)A(F)C(M)A(F)A(M)G(F)G(M)U(F)A(M)A(F)A(M) AH0645 SEQ ID NO: U(F)G(M)C(F)C(M)U(F)A(M)C(F)A(M)G(F)C(M)C SEQ ID NO: U(F)A(M)G(F)G(M)A(F)G(M)A(F)A(M)G(F)A(M)G(M)G 0.083 0.130 1932 (F)U(F)C(M)U(F)U(M)C(F)U(M)C(F)C(M)U(F)A(M) 1976 (F)C(M)U(F)G(M)U(F)A(M)G(F)G(M)C(F)A(M)C(F)G(M) AH0646 SEQ ID NO: A(F)C(M)A(F)G(M)C(F)C(M)U(F)C(M)U(F)U(M)C SEQ ID NO: U(F)A(M)U(F)U(M)G(F)U(M)A(F)G(M)G(F)A(M)G(M)A 0.101 0.257 1933 (F)U(F)C(M)C(F)U(M)A(F)C(M)A(F)A(M)U(F)A(M) 1977 (F)A(M)G(F)A(M)G(F)G(M)C(F)U(M)G(F)U(M)A(F)G(M) AH0647 SEQ ID NO: G(F)U(M)C(F)C(M)U(F)C(M)A(F)U(M)C(F)A(M)G SEQ ID NO: U(F)C(M)A(F)G(M)C(F)A(M)A(F)U(M)A(F)C(M)C(M)U 0.135 0.293 1934 (F)G(F)U(M)A(F)U(M)U(F)G(M)C(F)U(M)G(F)A(M) 1978 (F)G(M)A(F)U(M)G(F)A(M)G(F)G(M)A(F)C(M)U(F)C(M) AH0648 SEQ ID NO: A(F)G(M)G(F)A(M)G(F)C(M)C(F)A(M)G(F)U(M)C SEQ ID NO: U(F)C(M)C(F)C(M)A(F)C(M)A(F)A(M)A(F)G(M)G(M)A 0.177 0.355 1935 (F)C(F)U(M)U(F)U(M)G(F)U(M)G(F)G(M)G(F)A(M) 1979 (F)C(M)U(F)G(M)G(F)C(M)U(F)C(M)C(F)U(M)A(F)U(M) AH0649 SEQ ID NO: G(F)A(M)G(F)C(M)C(F)A(M)G(F)U(M)C(F)C(M)U SEQ ID NO: U(F)C(M)U(F)C(M)C(F)C(M)A(F)C(M)A(F)A(M)A(M)G 0.084 0.196 1936 (F)U(F)U(M)G(F)U(M)G(F)G(M)G(F)A(M)G(F)A(M) 1980 (F)G(M)A(F)C(M)U(F)G(M)G(F)C(M)U(F)C(M)C(F)U(M) AH0650 SEQ ID NO: C(F)C(M)A(F)G(M)U(F)C(M)C(F)U(M)U(F)U(M)G SEQ ID NO: A(F)U(M)C(F)U(M)C(F)U(M)C(F)C(M)C(F)A(M)C(M)A 0.065 0.126 1937 (F)U(F)G(M)G(F)G(M)A(F)G(M)A(F)G(M)A(F)U(M) 1981 (F)A(M)A(F)G(M)G(F)A(M)C(F)U(M)G(F)G(M)C(F)U(M) AH0651 SEQ ID NO: C(F)A(M)G(F)U(M)C(F)C(M)U(F)U(M)U(F)G(M)U SEQ ID NO: A(F)A(M)U(F)C(M)U(F)C(M)U(F)C(M)C(F)C(M)A(M)C 0.093 0.193 1938 (F)G(F)G(M)G(F)A(M)G(F)A(M)G(F)A(M)U(F)U(M) 1982 (F)A(M)A(F)A(M)G(F)G(M)A(F)C(M)U(F)G(M)G(F)C(M) AH0652 SEQ ID NO: U(F)G(M)G(F)G(M)A(F)G(M)A(F)G(M)A(F)U(M)U SEQ ID NO: A(F)C(M)A(F)A(M)A(F)U(M)C(F)C(M)C(F)C(M)A(M)A 0.170 0.380 1939 (F)G(F)G(M)G(F)G(M)A(F)U(M)U(F)U(M)G(F)U(M) 1983 (F)U(M)C(F)U(M)C(F)U(M)C(F)C(M)C(F)A(M)C(F)A(M) AH0653 SEQ ID NO: G(F)G(M)G(F)A(M)G(F)A(M)G(F)A(M)U(F)U(M)G SEQ ID NO: U(F)A(M)C(F)A(M)A(F)A(M)U(F)C(M)C(F)C(M)C(M)A 0.152 0.300 1940 (F)G(F)G(M)G(F)A(M)U(F)U(M)U(F)G(M)U(F)A(M) 1984 (F)A(M)U(F)C(M)U(F)C(M)U(F)C(M)C(F)C(M)A(F)C(M) AH0654 SEQ ID NO: G(F)A(M)G(F)A(M)G(F)A(M)U(F)U(M)G(F)G(M)G SEQ ID NO: U(F)G(M)U(F)A(M)C(F)A(M)A(F)A(M)U(F)C(M)C(M)C 0.094 0.176 1941 (F)G(F)A(M)U(F)U(M)U(F)G(M)U(F)A(M)C(F)A(M) 1985 (F)C(M)A(F)A(M)U(F)C(M)U(F)C(M)U(F)C(M)C(F)C(M) AH0655 SEQ ID NO: U(F)C(M)C(F)U(M)G(F)U(M)C(F)U(M)G(F)C(M)C SEQ ID NO: U(F)A(M)C(F)C(M)C(F)U(M)G(F)A(M)U(F)A(M)G(M)G 0.123 0.332 1942 (F)U(F)A(M)U(F)C(M)A(F)G(M)G(F)G(M)U(F)A(M) 1986 (F)C(M)A(F)G(M)A(F)C(M)A(F)G(M)G(F)A(M)U(F)A(M) AH0656 SEQ ID NO: C(F)A(M)G(F)G(M)C(F)U(M)C(F)U(M)G(F)A(M)A SEQ ID NO: G(F)A(M)U(F)U(M)U(F)C(M)A(F)U(M)A(F)G(M)U(M)U 0.098 0.176 1943 (F)C(F)U(M)A(F)U(M)G(F)A(M)A(F)A(M)U(F)C(M) 1987 (F)C(M)A(F)G(M)A(F)G(M)C(F)C(M)U(F)G(M)C(F)C(M) AH0657 SEQ ID NO: G(F)A(M)G(F)G(M)A(F)U(M)A(F)U(M)G(F)U(M)C SEQ ID NO: G(F)U(M)U(F)U(M)G(F)A(M)U(F)G(M)A(F)U(M)G(M)A 0.147 0.338 1944 (F)A(F)U(M)C(F)A(M)U(F)C(M)A(F)A(M)A(F)C(M) 1988 (F)C(M)A(F)U(M)A(F)U(M)C(F)C(M)U(F)C(M)U(F)G(M) AH0658 SEQ ID NO: U(F)G(M)G(F)G(M)U(F)C(M)U(F)G(M)A(F)G(M)G SEQ ID NO: U(F)G(M)A(F)G(M)U(F)C(M)A(F)A(M)G(F)A(M)C(M)C 0.103 0.203 1945 (F)U(F)C(M)U(F)U(M)G(F)A(M)C(F)U(M)C(F)A(M) 1989 (F)U(M)C(F)A(M)G(F)A(M)C(F)C(M)C(F)A(M)C(F)A(M) AH0659 SEQ ID NO: A(F)C(M)U(F)C(M)A(F)A(M)C(F)G(M)A(F)G(M)A SEQ ID NO: U(F)U(M)U(F)C(M)A(F)A(M)G(F)U(M)G(F)C(M)U(M)C 0.066 0.084 1946 (F)G(F)C(M)A(F)C(M)U(F)U(M)G(F)A(M)A(F)A(M) 1990 (F)U(M)C(F)G(M)U(F)U(M)G(F)A(M)G(F)U(M)C(F)A(M) AH0660 SEQ ID NO: C(F)U(M)C(F)A(M)A(F)C(M)G(F)A(M)G(F)A(M)G SEQ ID NO: U(F)U(M)U(F)U(M)C(F)A(M)A(F)G(M)U(F)G(M)C(M)U 0.067 0.066 1947 (F)C(F)A(M)C(F)U(M)U(F)G(M)A(F)A(M)A(F)A(M) 1991 (F)C(M)U(F)C(M)G(F)U(M)U(F)G(M)A(F)G(M)U(F)C(M) AH0661 SEQ ID NO: U(F)C(M)A(F)A(M)C(F)G(M)A(F)G(M)A(F)G(M)C SEQ ID NO: A(F)U(M)U(F)U(M)U(F)C(M)A(F)A(M)G(F)U(M)G(M)C 0.058 0.074 1948 (F)A(F)C(M)U(F)U(M)G(F)A(M)A(F)A(M)A(F)U(M) 1992 (F)U(M)C(F)U(M)C(F)G(M)U(F)U(M)G(F)A(M)G(F)U(M) AH0662 SEQ ID NO: A(F)A(M)C(F)G(M)A(F)G(M)A(F)G(M)C(F)A(M)C SEQ ID NO: U(F)C(M)A(F)U(M)U(F)U(M)U(F)C(M)A(F)A(M)G(M)U 0.046 0.091 1949 (F)U(F)U(M)G(F)A(M)A(F)A(M)A(F)U(M)G(F)A(M) 1993 (F)G(M)C(F)U(M)C(F)U(M)C(F)G(M)U(F)U(M)G(F)A(M) AH0663 SEQ ID NO: A(F)C(M)G(F)A(M)G(F)A(M)G(F)C(M)A(F)C(M)U SEQ ID NO: U(F)U(M)C(F)A(M)U(F)U(M)U(F)U(M)C(F)A(M)A(M)G 0.053 0.068 1950 (F)U(F)G(M)A(F)A(M)A(F)A(M)U(F)G(M)A(F)A(M) 1994 (F)U(M)G(F)C(M)U(F)C(M)U(F)C(M)G(F)U(M)U(F)G(M) AH0664 SEQ ID NO: C(F)G(M)A(F)G(M)A(F)G(M)C(F)A(M)C(F)U(M)U SEQ ID NO: U(F)U(M)U(F)C(M)A(F)U(M)U(F)U(M)U(F)C(M)A(M)A 0.057 0.076 1951 (F)G(F)A(M)A(F)A(M)A(F)U(M)G(F)A(M)A(F)A(M) 1995 (F)G(M)U(F)G(M)C(F)U(M)C(F)U(M)C(F)G(M)U(F)U(M) AH0665 SEQ ID NO: G(F)A(M)G(F)A(M)G(F)C(M)A(F)C(M)U(F)U(M)G SEQ ID NO: A(F)U(M)U(F)U(M)C(F)A(M)U(F)U(M)U(F)U(M)C(M)A 0.062 0.082 1952 (F)A(F)A(M)A(F)A(M)U(F)G(M)A(F)A(M)A(F)U(M) 1996 (F)A(M)G(F)U(M)G(F)C(M)U(F)C(M)U(F)C(M)G(F)U(M) AH0666 SEQ ID NO: A(F)G(M)A(F)G(M)C(F)A(M)C(F)U(M)U(F)G(M)A SEQ ID NO: C(F)A(M)U(F)U(M)U(F)C(M)A(F)U(M)U(F)U(M)U(M)C 0.062 0.083 1953 (F)A(F)A(M)A(F)U(M)G(F)A(M)A(F)A(M)U(F)G(M) 1997 (F)A(M)A(F)G(M)U(F)G(M)C(F)U(M)C(F)U(M)C(F)G(M) AH0667 SEQ ID NO: C(F)U(M)A(F)A(M)G(F)A(M)G(F)A(M)U(F)C(M)U SEQ ID NO: U(F)G(M)C(F)U(M)U(F)U(M)G(F)A(M)C(F)C(M)A(M)G 0.093 0.131 1954 (F)G(F)G(M)U(F)C(M)A(F)A(M)A(F)G(M)C(F)A(M) 1998 (F)A(M)U(F)C(M)U(F)C(M)U(F)U(M)A(F)G(M)A(F)C(M) AH0668 SEQ ID NO: C(F)U(M)G(F)G(M)U(F)C(M)A(F)A(M)A(F)G(M)C SEQ ID NO: G(F)U(M)A(F)U(M)C(F)C(M)A(F)G(M)U(F)U(M)G(M)C 0.157 0.319 1955 (F)A(F)A(M)C(F)U(M)G(F)G(M)A(F)U(M)A(F)C(M) 1999 (F)U(M)U(F)U(M)G(F)A(M)C(F)C(M)A(F)G(M)A(F)U(M) AH0669 SEQ ID NO: A(F)A(M)G(F)C(M)A(F)A(M)C(F)U(M)G(F)G(M)A SEQ ID NO: A(F)G(M)A(F)U(M)C(F)U(M)A(F)G(M)U(F)A(M)U(M)C 0.083 0.126 1956 (F)U(F)A(M)C(F)U(M)A(F)G(M)A(F)U(M)C(F)U(M) 2000 (F)C(M)A(F)G(M)U(F)U(M)G(F)C(M)U(F)U(M)U(F)G(M) AH0670 SEQ ID NO: A(F)G(M)C(F)A(M)A(F)C(M)U(F)G(M)G(F)A(M)U SEQ ID NO: A(F)A(M)G(F)A(M)U(F)C(M)U(F)A(M)G(F)U(M)A(M)U 0.071 0.129 1957 (F)A(F)C(M)U(F)A(M)G(F)A(M)U(F)C(M)U(F)U(M) 2001 (F)C(M)C(F)A(M)G(F)U(M)U(F)G(M)C(F)U(M)U(F)U(M) AH0671 SEQ ID NO: G(F)C(M)A(F)A(M)C(F)U(M)G(F)G(M)A(F)U(M)A SEQ ID NO: U(F)A(M)A(F)G(M)A(F)U(M)C(F)U(M)A(F)G(M)U(M)A 0.115 0.181 1958 (F)C(F)U(M)A(F)G(M)A(F)U(M)C(F)U(M)U(F)A(M) 2002 (F)U(M)C(F)C(M)A(F)G(M)U(F)U(M)G(F)C(M)U(F)U(M) AH0672 SEQ ID NO: A(F)U(M)C(F)U(M)U(F)A(M)C(F)A(M)U(F)C(M)U) SEQ ID NO: A(F)A(M)A(F)G(M)A(F)G(M)C(F)U(M)G(F)C(M)A(M)G 0.072 0.093 1959 (F)G(FC(M)A(F)G(M)C(F)U(M)C(F)U(M)U(F)U(M) 2003 (F)A(M)U(F)G(M)U(F)A(M)A(F)G(M)A(F)U(M)C(F)U(M) AH0673 SEQ ID NO: U(F)A(M)C(F)A(M)U(F)C(M)U(F)G(M)C(F)A(M)G SEQ ID NO: G(F)A(M)A(F)G(M)A(F)A(M)A(F)G(M)A(F)G(M)C(M)U 0.089 0.112 1960 (F)C(F)U(M)C(F)U(M)U(F)U(M)C(F)U(M)U(F)C(M) 2004 (F)G(M)C(F)A(M)G(F)A(M)U(F)G(M)U(F)A(M)A(F)G(M) AH0674 SEQ ID NO: A(F)C(M)A(F)U(M)C(F)U(M)G(F)C(M)A(F)G(M)C SEQ ID NO: A(F)G(M)A(F)A(M)G(F)A(M)A(F)A(M)G(F)A(M)G(M)C 0.067 0.082 1961 (F)U(F)C(M)U(F)U(M)U(F)C(M)U(F)U(M)C(F)U(M) 2005 (F)U(M)G(F)C(M)A(F)G(M)A(F)U(M)G(F)U(M)A(F)A(M) AH0675 SEQ ID NO: C(F)A(M)U(F)C(M)U(F)G(M)C(F)A(M)G(F)C(M)U SEQ ID NO: A(F)A(M)G(F)A(M)A(F)G(M)A(F)A(M)A(F)G(M)A(M)G 0.098 0.114 1962 (F)C(F)U(M)U(F)U(M)C(F)U(M)U(F)C(M)U(F)U(M) 2006 (F)C(M)U(F)G(M)C(F)A(M)G(F)A(M)U(F)G(M)U(F)A(M) AH0676 SEQ ID NO: A(F)U(M)C(F)U(M)G(F)C(M)A(F)G(M)C(F)U(M)C SEQ ID NO: A(F)A(M)A(F)G(M)A(F)A(M)G(F)A(M)A(F)A(M)G(M)A 0.093 0.144 1963 (F)U(F)U(M)U(F)C(M)U(F)U(M)C(F)U(M)U(F)U(M) 2007 (F)G(M)C(F)U(M)G(F)C(M)A(F)G(M)A(F)U(M)G(F)U(M) AH0677 SEQ ID NO: U(F)C(M)U(F)G(M)C(F)A(M)G(F)C(M)U(F)C(M)U SEQ ID NO: C(F)A(M)A(F)A(M)G(F)A(M)A(F)G(M)A(F)A(M)A(M)G 0.084 0.093 1964 (F)U(F)U(M)C(F)U(M)U(F)C(M)U(F)U(M)U(F)G(M) 2008 (F)A(M)G(F)C(M)U(F)G(M)C(F)A(M)G(F)A(M)U(F)G(M) AH0678 SEQ ID NO: C(F)U(M)G(F)C(M)A(F)G(M)C(F)U(M)C(F)U(M)U SEQ ID NO: U(F)C(M)A(F)A(M)A(F)G(M)A(F)A(M)G(F)A(M)A(M)A 0.089 0.100 1965 (F)U(F)C(M)U(F)U(M)C(F)U(M)U(F)U(M)G(F)A(M) 2009 (F)G(M)A(F)G(M)C(F)U(M)G(F)C(M)A(F)G(M)A(F)U(M) AH0679 SEQ ID NO: U(F)G(M)C(F)A(M)G(F)C(M)U(F)C(M)U(F)U(M)U SEQ ID NO: U(F)U(M)C(F)A(M)A(F)A(M)G(F)A(M)A(F)G(M)A(M)A 0.101 0.158 1966 (F)C(F)U(M)U(F)C(M)U(F)U(M)U(F)G(M)A(F)A(M) 2010 (F)A(M)G(F)A(M)G(F)C(M)U(F)G(M)C(F)A(M)G(F)A(M) AH0680 SEQ ID NO: G(F)C(M)A(F)G(M)C(F)U(M)C(F)U(M)U(F)U(M)C SEQ ID NO: A(F)U(M)U(F)C(M)A(F)A(M)A(F)G(M)A(F)A(M)G(M)A 0.086 0.112 1967 (F)U(F)U(M)C(F)U(M)U(F)U(M)G(F)A(M)A(F)U(M) 2011 (F)A(M)A(F)G(M)A(F)G(M)C(F)U(M)G(F)C(M)A(F)G(M) AH0681 SEQ ID NO: C(F)A(M)G(F)C(M)U(F)C(M)U(F)U(M)U(F)C(M)U SEQ ID NO: A(F)A(M)U(F)U(M)C(F)A(M)A(F)A(M)G(F)A(M)A(M)G 0.088 0.119 1968 (F)U(F)C(M)U(F)U(M)U(F)G(M)A(F)A(M)U(F)U(M) 2012 (F)A(M)A(F)A(M)G(F)A(M)G(F)C(M)U(F)G(M)C(F)A(M) AH0682 SEQ ID NO: U(F)U(M)G(F)A(M)A(F)U(M)U(F)U(M)C(F)C(M)U SEQ ID NO: A(F)C(M)A(F)U(M)A(F)C(M)A(F)G(M)A(F)U(M)A(M)G 0.052 0.064 1969 (F)A(F)U(M)C(F)U(M)G(F)U(M)A(F)U(M)G(F)U(M) 2013 (F)G(M)A(F)A(M)A(F)U(M)U(F)C(M)A(F)A(M)A(F)G(M) AH0683 SEQ ID NO: U(F)C(M)C(F)U(M)A(F)U(M)C(F)U(M)G(F)U(M)A SEQ ID NO: U(F)A(M)G(F)G(M)C(F)A(M)G(F)A(M)C(F)A(M)U(M)A 0.062 0.089 1970 (F)U(F)G(M)U(F)C(M)U(F)G(M)C(F)C(M)U(F)A(M) 2014 (F)C(M)A(F)G(M)A(F)U(M)A(F)G(M)G(F)A(M)A(F)A(M) AH0684 SEQ ID NO: A(F)U(M)C(F)U(M)G(F)U(M)A(F)U(M)G(F)U(M)C SEQ ID NO: U(F)A(M)A(F)U(M)U(F)A(M)G(F)G(M)C(F)A(M)G(M)A 0.055 0.083 1971 (F)U(F)G(M)C(F)C(M)U(F)A(M)A(F)U(M)U(F)A(M) 2015 (F)C(M)A(F)U(M)A(F)C(M)A(F)G(M)A(F)U(M)A(F)G(M) AH0685 SEQ ID NO: U(F)C(M)U(F)G(M)U(F)A(M)U(F)G(M)U(F)C(M)U SEQ ID NO: U(F)U(M)A(F)A(M)U(F)U(M)A(F)G(M)G(F)C(M)A(M)G( 0.073 0.099 1972 (F)G(F)C(M)C(F)U(M)A(F)A(M)U(F)U(M)A(F)A(M) 2016 F)A(M)C(F)A(M)U(F)A(M)C(F)A(M)G(F)A(M)U(F)A(M) AH0686 SEQ ID NO: C(F)U(M)G(F)U(M)A(F)U(M)G(F)U(M)C(F)U(M)G SEQ ID NO: U(F)U(M)U(F)A(M)A(F)U(M)U(F)A(M)G(F)G(M)C(M)A 0.148 0.305 1973 (F)C(F)C(M)U(F)A(M)A(F)U(M)U(F)A(M)A(F)A(M) 2017 (F)G(M)A(F)C(M)A(F)U(M)A(F)C(M)A(F)G(M)A(F)U(M) AH0687 SEQ ID NO: G(F)U(M)C(F)U(M)G(F)C(M)C(F)U(M)A(F)A(M)U SEQ ID NO: U(F)A(M)U(F)U(M)U(F)U(M)U(F)U(M)U(F)A(M)A(M)U 0.078 0.158 1974 (F)U(F)A(M)A(F)A(M)A(F)A(M)A(F)A(M)U(F)A(M) 2018 (F)U(M)A(F)G(M)G(F)C(M)A(F)G(M)A(F)C(M)A(F)U(M)

This application was filed based on Japanese Patent Application No. 2017-108502 (filing date: May 31, 2017), the entire contents of which are incorporated herein by reference.

Owing to the present invention, it is possible to provide a nucleic acid having an activity to suppress expression of APCS and a pharmaceutical composition comprising the nucleic acid as an active ingredient. The nucleic acid and pharmaceutical composition of the present invention can suppress expression of APCS and be used as a therapeutic or prophylactic agent for amyloid-related diseases.

Sequence Listing Free Text

SEQ ID NO: 1 represents the full-length base sequence of the 2nd strand cDNA of APCS.

SEQ ID NOs: 2 to 644 represent the base sequences of sense-strand nucleic acids.

SEQ ID NOs: 645 to 1287 represent the base sequences of antisense-strand nucleic acids.

SEQ ID NOs: 1288 to 1930 represent the base sequences of target APCS mRNA sequences.

SEQ ID NOs: 1931 to 1974 represent the base sequences of sense-strand nucleic acids.

SEQ ID NOs: 1975 to 2018 represent the base sequences of the antisense-strand nucleic acids. 

1. A double-stranded nucleic acid for suppressing expression of APCS gene, the double-stranded nucleic acid consisting of a sense-strand nucleic acid and an antisense-strand nucleic acid and comprising a double-strand region having at least 11 base pairs, wherein an oligonucleotide chain having a chain length of at least 17 nucleotides and at most 30 nucleotides in the antisense-strand nucleic acid is complementary to a target APCS mRNA sequence comprising a base sequence set forth in any one of SEQ ID NOS: 1288 to
 1930. 2. The double-stranded nucleic acid according to claim 1, wherein the double-strand region has 11 to 27 base pairs and a nucleotide at position 2 counted from a 5′ end of the antisense-strand nucleic acid is complementary to a deoxyribonucleotide at position 2 counted from a 3′ end of the target APCS mRNA sequence.
 3. The double-stranded nucleic acid according to claim 1, wherein a 3′ end of the sense-strand nucleic acid and a 5′ end of the antisense-strand nucleic acid and/or the 5′ end of the sense-strand nucleic acid and the 3′ end of the antisense-strand nucleic acid form a blunt end.
 4. The double-stranded nucleic acid according to claim 1, wherein the sense-strand nucleic acid has a chain length of 21 nucleotides and the antisense-strand nucleic acid has a chain length of 21 nucleotides.
 5. The double-stranded nucleic acid according to claim 4, comprising a double-strand region having 19 base pairs, wherein 40 to 65% of the nucleotides in the double-strand region are 2′-O-methyl modified nucleotides.
 6. The double-stranded nucleic acid according to claim 1, wherein the antisense-strand nucleic acid comprises a base sequence set forth in any one of SEQ ID NOS: 645 to 1287 and 1975 to
 2018. 7. The double-stranded nucleic acid according to claim 1, wherein the sense-strand nucleic acid comprises a base sequence set forth in any one of SEQ ID NOS: 2 to 644 and 1931 to
 1974. 8. The double-stranded nucleic acid according to claim 1, wherein the sense-strand nucleic acid comprises a base sequence set forth in any one of SEQ ID NOS: 2 to 644 and 1931 to 1974, and correspondingly thereto, the antisense-strand nucleic acid comprises a base sequence set forth in any one of SEQ ID NOS: 645 to 1287 and 1975 to
 2018. 9. The double-stranded nucleic acid according to claim 1, comprising a ligand.
 10. A single-stranded nucleic acid consisting only of the antisense-strand nucleic acid of the double-stranded nucleic acid according to claim
 1. 11. A pharmaceutical composition comprising the nucleic acid according to claim
 1. 12. A method for treating a disorder mediated by APCS-containing amyloid fibrils, comprising a step of administering a therapeutically effective amount of the nucleic acid according to claim 1 to a human in need of such a treatment.
 13. The method according to claim 12, wherein the disorder is an amyloid-related disease.
 14. A method for treating a disorder mediated by APCS-containing amyloid fibrils, comprising a step of administering a therapeutically effective amount of the pharmaceutical composition according to claim 11 to a human in need of such a treatment.
 15. The method according to claim 14, wherein the disorder is an amyloid-related disease.
 16. A method for suppressing expression of APCS gene, comprising a step of administering a therapeutically effective amount of a double-stranded nucleic acid for suppressing expression of APCS gene, the double-stranded nucleic acid consisting of a sense-strand nucleic acid and an antisense-strand nucleic acid and comprising a double-strand region having at least 11 base pairs, wherein an oligonucleotide chain having a chain length of at least 17 nucleotides and at most 30 nucleotides in the antisense-strand nucleic acid is complementary to a target APCS mRNA sequence comprising a base sequence set forth in any one of SEQ ID NOS: 1288 to 1930 to a human in need of such a treatment. 